CN110709099A - Immunogenic compositions for modulating the immune system and methods of treating bacterial infections in subjects - Google Patents
Immunogenic compositions for modulating the immune system and methods of treating bacterial infections in subjects Download PDFInfo
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- CN110709099A CN110709099A CN201880023729.7A CN201880023729A CN110709099A CN 110709099 A CN110709099 A CN 110709099A CN 201880023729 A CN201880023729 A CN 201880023729A CN 110709099 A CN110709099 A CN 110709099A
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to a pharmaceutical product comprising an immunogenic composition for modulating the immune system, the immunogenic composition comprising a therapeutically effective amount of an immune response displacer (IRS) containing two or more immunologically active antigenic agents exhibiting a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) and/or a Stress Response Signal (SRS), in combination with an antibiotic and one or more physiologically acceptable carriers, excipients, diluents or solvents. In other embodiments, the invention relates to methods of treating severe bacterial infections, sepsis and modulating the immune system.
Description
Cross Reference to Related Applications
This application is a continuation-in-part application of U.S. patent application serial No. 14/006,077 filed on day 10, 23, 2013, a national phase of international application PCT/BR2012/000072 filed on day 19, 2012 (designating the united states of america), which also includes the requirements for priority of brazilian patent application No. PI 1100857-1 filed on day 18, 2011, in accordance with 35u.s.c. § 119(a) and § 365(b), all of which are incorporated herein by reference in their entirety.
Technical Field
The present invention relates to an immunogenic composition for modulating the immune system comprising a therapeutically effective amount of an immune Response displacer (IRS) comprising two or more immunologically active antigenic agents (1) presenting a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) and/or a Stress Response Signal (SRS) and one or more physiologically acceptable carriers, excipients, diluents or solvents.
The composition of the invention comprises an immunologically active antigenic agent (1) presenting a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) and/or a Stress Response Signal (SRS), selected from: (A) an antigenic agent having a molecular pattern associated with bacteria; (B) an antigenic agent having a molecular pattern associated with a virus; (C) antigenic agents with molecular patterns related to fungi and yeast; (D) an antigenic agent having a molecular pattern associated with a protozoan; (E) an antigenic agent with a molecular pattern associated with multicellular parasites and/or (F) an antigenic agent with a molecular pattern associated with prions.
Background
Starting from the pioneering discovery of antibiotics in the first half of the 20 th century, new antibiotics, semi-synthetic antibiotics, and new chemotherapeutic agents with antibacterial activity against intracellular and extracellular bacteria have been developed on a large scale. These developments have transformed the medical history to enable a broad cure for the vast majority of bacterial infectious diseases that are harmful to humans.
Discovery of antibiotics and other drugs
Thus, the discovery of antibiotics is an important milestone and watershed, as infections can be resolved and cured in a specific and well-defined causal and quantifiable manner at the time of colonization (establish). This finding greatly expands the capabilities of medical treatment, creating a tremendous positive impact on human health and longevity. The discovery of antibiotics in disease evolution and treatment profoundly influences the researchers' success and thinking in this experimental model (Reeves G, to dd I.characteristics on immunology. second edition: Blackwell Scientific Publications, 1991; Neto VA, Nicodemo AC, Lopes HV.Antibi tics na PR tic meca, sixth edition: Sarvier, 2007; Murray PR, Rosenthal KS, Pfaller MA.Microbiolia Mega. fifth edition: MoTraby, 2006; bublli LR, Alterthum F.Microbiolia. fifth edition: Atheu Editora, 2008).
Antibiotics have been successfully developed through the development and use of antifungal, antiparasitic and antiviral agents. The "resistant" drug ("anti" drug) model is a gold standard experimental model due to the great success of anti-etiological drugs and extends to diseases with unknown etiology for their physiopathological processes and to very similar autologous tumor cells with lower specificity, lower selectivity and lower effectiveness in the following respects:
anti-allergic;
anti-inflammatory;
anti-immunity (immunosuppression);
anti-tumor (cytotoxic); and
an anti-hormone.
Thus, new "resistant" drugs bring a great capacity for medical intervention, with many benefits, with a clear and partial cure, prolonging the lives of untreated patients, but also with a high incidence due to the side effects associated with the lack of specificity for the pathophysiology of the disease.
Innate immunity
In addition to preventing microorganisms from entering and arresting their colonization, innate immunity has another recently discovered important function: "self" and "non-self" are distinguished by pattern recognition capabilities associated with alerts and commands to initiate or suppress a combined immune response against invading microorganisms or to prevent, repair or suppress conditions of destruction or self-invasion of the body (e.g., in trauma, autoimmune and allergic or other diseases).
This dual capability has previously been mistakenly attributed to adaptive immunity. Through its own germinal receptors, the innate immunity recognizes invading pathogenic microorganisms, autologous or even allogeneic tumor cells, or allogeneic or xenografts as "non-self", confirming that they do not belong to the organism. From this point on, it triggers an alarm and combines innate and adaptive immune responses to eliminate them or inhibit adverse reactions to the human or animal organism (Goldsby RA, kit TJ, Osborn B. Immunology de kuby sixth edition: ARTMED; 2008, page 704; Janeway C, transactions P, WalportM, Slhlomk MJ. Immunobiology five edition: Garland pub., page 732; Volteri JC. Immunology na. formal: american. distribution. 2009; Janeway CA, Jr., middle mouse R. Informa. evaluation. Annual review of immunology, 2002; 20:197-216.EP 2002/02/28; arrival TLsub.2002. III. Biotech. M. J. III. Biotech. distribution. WO 26. 10. III. Biotech. WO 26. 11. 10. Biotech. III. Biotech. 2002; Nature et 11. Biotech. III. Biotech. III. Biotech. No. 11. 7. 10. 7. Nature No. 11. 7. Nature et Biotech. 11. III. Biotech. 11. 7. Biotech. 11. III. Biotech. 11. M. III. M. 11. 7. Biotech. 11. 7. M. 11. Biotech. 11. III. Biotech. 7. III. Biotech. 11. No. (Biotech. 11. Biotech., LaVine D, Beutler b. toll-like receptors. current biology: cb.2011; 21, (13) R488-93.Epub2011/07/12 (1).
The "non-self" recognition pattern of invasive bacteria is performed by sentinel cells represented by epithelial, mucosal and stromal cells (e.g., pericytes, dendritic cells, macrophages and fibroblasts, etc.). These cells are strategically distributed throughout the body, with PRRs (pattern recognition receptors) and DRRs (danger recognition receptors) and SRRs (stress response receptors) which are able to recognize a) standard recognition molecules, respectively, which are characteristic of a wide range of microorganisms, B) specific patterns for changes in chemical and physical and metabolic stress of so-called inert substances (inert substance), such as the release of free radicals and histochemical changes due to ionizing radiation or chemicals etc., and c) stress receptor signals, which recognize viral, starvation, ER stress and oxidative stress (Pulendran, B Annual Review Immunology 2015).
PRRs do not distinguish between a particular single microorganism, but can distinguish between microorganisms outside the human body. Each PRR receptor can bind several different pathogens, recognizing carbohydrates, lipids, peptides and nucleic acids from bacteria, viruses, fungi or parasites not found in humans or animals as PAMPs (pathogen-associated molecular patterns).
DRR distinguishes the presence of tissue damage, which is a dangerous condition caused by non-living or inert agents. Through these receptor recognition, DRRs recognize DAMP (risk associated molecular patterns) associated with tissue damage caused by toxic substances, radiation, or trauma in the tissue that trigger metabolic stress, free radical release, and chemical changes.
SRR (Stress receptor) recognizes metabolic Stress signals caused by environmental insults (e.g., viral infection or viral effective vaccine, amino acid starvation, ER (endoplasmic reticulum) Stress, oxidative Stress) through evolutionary conserved Stress sensing mechanisms, which consist of, for example, recently discovered Integrated Stress Response (Integrated Stress Response) ISR (Janeway C, transactions P, ports M, Slhlomchik MJ.immunobiology five edition: Garland pub., 2001. page 732; Matzinger P. the model: a recycled sensor of science.2002; 296(5566):301-5. Epubb 2002/04/16; Beutler BA. TLubr. and nature animal CB. blood 2009; 113(7): 1399-6356; 2008/09/02; latex. E. 2011. Bior. receptor; Beutler et al. 2011. 7. current CB. 13. Tojr 3. 2011/07/12).
Thus, sentry cells act through their PRRs and their DRRs and SRRs in a classification that belongs to them ("self") or not ("non-self") and trigger inflammation and immune responses by recognizing PAMPs of invasive pathogens and multiply-triggered DAMPs by changes in tumor cells, inert and toxic substances or trauma, or stress-response signals in infections by ISRs that lead to truly dangerous situations in humans and animals.
These activated sentry cells immediately send out an alarm signal, triggering an innate immune response through the NF-kB (nuclear factor-kB) signaling system, leading to the secretion of pro-differentiated cytokines and IRF signaling systems, producing type I alpha and beta interferons. These cytokines act together on cells and blood vessels, causing a local inflammatory process, primarily for inclusion in invaders, autologous (tumor cells), allogenic (microorganisms, prions, transplants and grafts) or allogeneic (transplants and grafts), or for the repair of dangerous situations. This competition can occur by the pre-existing antibodies making acute phase proteins susceptible to phagocytosis and by leukocytes and macrophages, which phagocytose and begin to destroy extracellular and intracellular microorganisms, respectively, or by eliminating any type of other causative substance.
Interaction and integration of innate and adaptive immunity
At the same time, at the site of invasion, invasion and inflammation, innate immune sentinel cells with APC (antigen presenting cell) action, such as dendritic cells and macrophages, have phagocytosis and pinocytosis against microorganisms or tumor cells, or transplanted cells, and other invaders and have their antigens. These APC cells sensitized with antigen migrate to regional lymph nodes and activate them. Activated and mature APC cells in the reactive lymph nodes present antigens to lymphocytes, releasing cytokines, thereby inducing, coordinating, polarizing, amplifying, and maintaining an adaptive immune response specific to invading bacteria, tumor cells or transplanted cells or other invaders, allowing it to be defeated and eliminated where feasible, thereby ultimately curing the infection or inflammation, repair and regeneration, or wound healing (1) (3).
Thus, these immune mechanisms fight disease in an integrated and synergistic manner through innate and adaptive primary or secondary responses, using sentinel cells, APC functional sentinels and innate immune effectors, the combination of cells and molecules with cellular and molecular effectors of adaptive immunity by lymphocytes, cytokines and antibodies, respectively.
Thus, in the case of an infection or an immune response to any type of invader, the interaction of both innate and adaptive immunity helps to fight the disease in an integrated and synergistic manner. The integration of both occurs initially through the action of innate immune cells with APC functions (e.g. dendritic cells and macrophages), but mainly through the activation of dendritic cells, which are cells capable of initiating adaptive immunity against primary infectious agents or parasitic agents, effectively protecting the body (2, 3). In secondary response memory, cellular control induces a silent immune process of complete protection (1,2,3,14,26,38,54,56,57,58, 65).
Macrophages also function as APC cells, but are more specific and participate as part of the effector loop for phagocytosis and elimination of microorganisms. B lymphocytes, which are also APC cells at maturation, are the most well understood role of presenting antigen to T lymphocytes in the framework of the cooperation of the two lymphocytes to produce antibodies against T-dependent antigens, as well as secondary antibody responses in lymph nodes and bone marrow. Like other bone marrow cells, macrophages are also involved in suppressing immune responses, mainly chronic or acute infections, and in the case of chronic infections or tumors, appear to be detrimental to the body's defenses because they suppress immune responses and cause chronic infections or tumor promotion.
When the co-stimulatory molecule is not expressed on the surface of the APC, only the first signal given by the TCR occurs due to the absence of the alarm signal characterized by the activation of PRRs, DAMPs and SRRs in the absence of PAMPs, DAMPs and SRS. After the TCR binds to the antigen, the T lymphocyte becomes tolerant to the specific antigen that is presented and that halts the immune response in the absence of a second signal.
On the other hand, the CD40L molecule of activated T lymphocytes, when it binds to the CD40 molecule on APC cells, significantly increases the expression of CD80 and CD86 molecules, increasing the instant effect and thus only occurs when the adaptive T response has been involved in the defense of the body. The third signal given by a cytokine such as IL-1 is typically given by APC cells after costimulatory molecule binding and secondary signaling. IL-1 released by APC cells acts on lymphocytes, resulting in complete expression of the receptor for IL2 and production of IL2 and other polar cytokines by naive or memory lymphocytes, which are involved in initiating clonal selection and expansion (naive) or proliferation (secondary) of memory clones in response.
Thus, activation of innate immunity by pathogens or by invasion is critical to the release of secondary and tertiary signals and the development of potentially effective immunity by sufficient activation of T lymphocytes involved in the response. In the absence of the second and third signals, the response is halted and tolerance specific to the presented antigen is developed.
At the same time, neutrophils, monocytes and macrophages trigger an action on bacteria and other infectious agents through the attachment of PAMPs to PRRs, SRS on Antigen Presenting Cells (APCs), which activate local and newly arriving or optimally activated dendritic cells and macrophages by memory cells. These cells phagocytose and pinocytose bacteria and bacterial antigens, process them and begin the maturation process. The activated and mature dendritic cells now migrate to regional lymph nodes to present antigen and elicit an immune response against the invader.
PAMPs can remodel lymph node supply arterioles alone and induce lymph node hypertrophy, which is essential for the development of an effective primary adaptive response (4, 5). In secondary reactions to activation and sensitization by DC cells in inflammatory areas, effector memory CD4-CD40-L + cells are transferred by HEV into reactive lymph nodes in a CD62P dependent manner and allow dendritic cells to be used for T cells to elicit weak antigens, tolerant antigens and autoantigens that elicit autoimmune diseases, or to improve immune responses in ongoing infections or neoplastic diseases (4). Also in the inflammatory region, the effect memory CD 8T cells secrete CCL3, which in turn activates MPCs to produce TNF α that can induce PMNN and other MFCs to produce ROIs and clear intracellular bacteria. Unrelated intracellular pathogens sensitive to ROI can also be cleared by alternative activation in overlapping diseases or overlapping immune responses (6, 7).
Mature antigen-sensitized APC cells, particularly dendritic cells in lymph nodes, cooperate with T and B lymphocytes and initiate adaptive primary or secondary responses (1). Dendritic cells are the most potent cells for antigen presentation and are the only APC cells capable of activating the original CD4T lymphocyte and initiating a new immune response (2, 3).
After about 7 days in the lymph nodes, the cooperation between the blank CD4 lymphocyte CD4-Th0 (which became T CD4 Th2 or Tfh) and B lymphocytes and antigen presenting dendritic cells initiates differentiation of specifically sensitized B lymphocytes. These B cells, now activated, recognize bacterial antigens by surface immunoglobulins and, in cooperation with T helper cells, the cells after exposure to these antigens, proliferate, mature and differentiate into plasma cells, which now at the first moment outside the follicular node of the B cell area, enter and induce germinal center formation in activated lymph nodes and after differentiation and the secondary B cell response CD4Tfh in cooperation with other CD4T helper cells, release specific antibodies against the bacteria. In a secondary B cell response, long-lived plasma cells secrete T cell-dependent antibodies (1,6) (8,9) in the bone marrow after initial production in the lymph nodes. Generally, in the acute phase, all types of infections (bacteria, viruses, fungi and parasites) can be completely cured by regeneration and healing, or for the treatment of sequelae. They may also progress to incurable disease with or without control of the disease, chronic healing with or without sequelae, or death.
Polarization of immune response
The typical immune profile (immune profile) known and induced by dendritic cells produced by T CD4 cells by direct and indirect exposure to different cytokines is of the following four types (10-12):
a) a cellular Th1 profile, which results in cell-mediated cellular immunity (13);
b) a humoral Th2 profile, which results in antibody-mediated humoral immunity (13);
c) tissue or inflammatory Thl7 repertoire, which produces inflammatory tissue immunity, also mediated by cells and cytokines, which induces important inflammation that eliminates certain pathogens, and (13,14)
d) Treg/Trl profile, which ensures restoration of the state of physical balance by suppressing the three other profiles mentioned above to suppress immune response and control (13,15)
e) New profiles have been established, such as Tfh (follicular helper cells) for humoral responses (16), Th9 profiles for certain parasites such as helminths (17), Th22 for IL22 that produces a contribution to skin protection (17) or other profiles that may or may not be found fully established (18).
Thus, the spectrum (profile) ensures the defense of the organism and the elimination of pathogenic heterologous (infectious) agents invading and colonizing the body (neoplasia). The last typical spectrum ensures termination, balance, regeneration, safe return to normal of the immune response and prevents self-injury and allergies, and is therefore critical to human and animal health and protection as well as other spectra.
The polarization of the immune response is defined as the preponderance of certain immunological profiles, such as Th1 or Th2, at the expense of other profiles that are secondary or ineffective. This phenomenon occurs according to the type of attack the body is subjected to. That is, depending on the type of infection, pathology and stage of infection or pathology, different types of immune responses will dominate and may be cellular, humoral, tissue inflammatory or immunoregulatory responses, while other types of immune responses are suppressed, leading to polarization phenomena. (12)
By definition, there is a dominant spectrum in the polarization, but other non-dominant spectra are also required and expressed in a complementary manner, which will help to eliminate the disease. For example, tuberculosis is the appearance of Thl7 cells in the lung, which allow Thl cells to settle and can lead to a cure for this infection in the lung parenchyma (Stockinger, b. and veldheen, m.differentiation and function of Thl 7T cells. current Opinion in Immunology,19(3), page 281-286. 2007). In viral infection, CTL-repertoires of CTL cells destroy cells infected with the virus to eliminate the virus. However, antibodies are required to prevent the virus from infecting other healthy cells, thereby preventing the spread of infection. The cooperative assembly of the two profiles is essential for the healing of certain viral infections. In addition to the Tfh and Th2 profiles, certain intestinal infections with extracellular gram-negative bacilli require the generation of a complementary Thl7 profile in the final phase, capable of producing strong inflammation, to eliminate this type of bacteria. (12)
In summary, the fact that dendritic cells are the only professional APC cells capable of initiating a primary adaptive immune response and are most effective in triggering a secondary specific immune response, they therefore instruct, in either spectrum, innate and adaptive immune interactions and integration, producing an effective immune response that can cure the disease. Dendritic cells in conjunction with other APCs and sentry cells, in contact with different invaders of different functional states in the inflammatory site, lymph nodes, spleen, mucosa, are able to direct, coordinate, polarize and amplify the management of their adaptive immune response, primary and secondary (e.g. specific for peptides of the invading pathogen), in this case being best suited to eliminate ongoing infections (1,2, 3).
Thus, dendritic cells and other APC cells are key cells of the innate immune response, as they assess the nature of the autologous and heterologous pathogenic agents, i.e. the type of pathogen or colonizing cells, and, in addition to indicating an adaptive response with the spectrum and intensity required to eliminate the pathogen, are aided by sentry cells, which measure and assess the size of the heterologous or autologous invader, its spread, intensity and aggressiveness. In other words, innate immunity responds to aggression in the primary response through the action of T B and some NK memory cells, and is reconstructed in secondary, effective responses. (19)(20)(8,9,20-31)
Following differentiation, redifferentiation may occur by induction of the microenvironment and/or antigen type or its presentation, wherein the Th1 or Th2 profile may be exchanged for an inflammatory profile or an immunosuppressive profile, or vice versa. When the direction taken by the polarization is not the optimal direction to cure the infection process or neoplasia, this extreme plasticity of the immune system differentiates or re-differentiates in either direction, indicating a strategic window for manipulating the immune system during infection (32).
As an illustrative example we have seen what happens in severe infections or sepsis, which is sepsis induced by a large amount of inflammation induced by cytokines, induced by a large number of microorganisms contacting sentry cells throughout the body, also induces the Th17 profile, which in turn increases inflammation and thus becomes harmful, leading to tissue destruction, rather than inducing healing and paradoxically late immunosuppression through the Treg/Tr1 profile and depletion states. In these cases, the Thl7 spectrum, amplified by tissue destruction and inflammation, is involved in the development of clinical complications, such as severe ARDS (adult acute respiratory distress syndrome), lung shock, renal failure or shock, which all affect healing (4,33, 34).
Redifferentiation of the polarization of the Thl or Th2 spectrum, as well as suppression of a large amount of inflammation, is a logical and strategic approach for designing or preparing immunotherapies to attempt to address this massive and fatal condition during severe infection or sepsis, with significant mortality and morbidity, and for this, antibiotics and other antibacterial drugs, in current modalities (e.g., single modality), have disappointing anti-infective results. The same applies to severe intracellular bacterial, fungal, viral and parasitic infections with extensive tissue destruction and massive inflammation, often with poor prognosis.
Stimulation of immune responses using adjuvants
Human and animal organisms do not normally produce antibodies to soluble proteins and so require the use of so-called non-specific or unrelated adjuvants to achieve the desired immune response. In vaccination and vaccination applications, these adjuvants used from immunization consist of parts of microorganisms, mineral oil and other substances that activate innate immunity, which then give the necessary warning and control to develop the desired immune response against proteins or the vaccine (GOLDSBY RA, KINDTTJ, OSBORNE ba. imunogia DE kuby. sixth edition: ARTMED; 2008. page 704); (Janeway C, Travers P, port M, Slhlomchik MJ. immunology five edition: Garland Pub.; 2001. page 732); (VOLTARELLI JC. IMUNOLOGIA CLINICA NAPRATICAMEDICA: ATHENEU EDITORA; 2009); (Janeway CA, Jr., Medzhitov R. Natate immune reproduction of immunology.2002; 20:197-216.Epub 2002/02/28.); (Matzinger P. the danger model: arenewed sense of self. science.2002; 296(5566):301-5.Epub 2002/04/16.) (Steinman RM, Banchereau J. Taking polymeric cells in media. Nature.2007; 449(7161):19-26.Epub 2007/09/28.); (Beutler BA.TLRs and innatimmnity.blood.2009; 113(7):1399-407.Epub 2008/09/02.); (Moresco EM, LaVine D, Beutler B. toll-like receptors. Current biology: CB.2011; 21(13): R488-93.Epub 2011/07/12).
It should be noted that immunization with adjuvants, although the oldest and still one of the current features, are highly used and necessary for vaccination and immunological studies, and are considered to be only a useful non-specific effect. For over a century it has not envisaged a role in innate immunity, namely the distinction between "self" and "non-self" and its unique and fundamental ability to survive on human species and animals: instructions for signaling alarms and for initiating or not initiating, or suppressing, integrating, protecting or curing, innate and adaptive immune responses (GOLDSBY RA, kiddt TJ, OSBORNE ba. imunogiade kuby. sixth edition: ARTMED; 2008.704 p); (Janeway C, Travers P, Walport M, SlhlomchikMJ. immunology five edition: Garland Pub.; 2001.732P.); (VOLTARELLIJC. IMUNOLOGIA CLINICA NA PRATICA MEDICA: ATHENEU EDITORA; 2009); (Janeway CA, Jr., Medzhitov R. Natate immune reproduction of immunology.2002; 20:197-216.Epub 2002/02/28.); (Matzinger P. the danger model: a renewed sense of science.2002; 296(5566):301-5.Epub 2002/04/16.) (Steinman RM, BanchereauJ. Taking polymeric cells in media. Nature.2007; 449(7161):419-26.Epub 2007/09/28.); (Beutler BA.TLRs and nate immunity. blood.2009; 113(7):1399-407.Epub 2008/09/02.); (Moresco EM, LaVine D, Beutler B. toll-like receptors. Current biology: CB.2011; 21(13): R488-93.Epub 2011/07/12).
Treatment of severe infections, sepsis and septic shock
A typical example of an infectious disease today is that antimicrobial agents are toxic selective drugs that destroy or block pathogens, such as bacteria, fungi, viruses, and parasites, cause little harm to the host, and are responsible for the elimination of these agents. Therefore, they are traditionally used for monotherapy. (Reeves G, Todd I.characteristics on immunology, second edition: Blackwell Scientific Publications, 1991; Neto VA, Nicodemo AC, Lopes HV.Antibi [ sic ] meca [ sic ] sixth edition: Sarvier, 2007; Murray PR, Rosenthal KS, PfallerMA.Microbiolia [ sic ] meca [ sic ] fifth edition: Mosby, 2006; Bulsi LR, Alterthum F.Microbiolia [ sic ] fifth edition: Athenneu Editora, 2008).
Treatment of severe infections, sepsis and septic shock incorporates more than one antibiotic, avoids microbial resistance, and incorporates supportive measures to prevent or limit SIRS, ARSD or MODS or is aided by prophylactic vaccines. Thus, current research is primarily focused on new antibacterial drugs, drugs to prevent microbial resistance, and new medical or biological agents to inhibit or control pro-inflammatory and immunosuppressive microenvironments, and vaccines (34-41).
Paradoxically, detailed analysis of experimental models led to the current model of infectious disease, revealing an unexpected and unexpected different conclusion: in this model, there are 3 participants in the culture dish: pathogens, antibacterial drugs, and inert media, which do not interfere with the interaction of the first 2 components. In this case, if the drug is effective, we can say that the antibiotic eliminates or clears the pathogen in vitro.
However, in the context of in vivo correlation, there are 3 components: antibiotic drugs, pathogens and the human or animal body, which are not inert media and have an immune system that has the same task as antibiotics, i.e. which also prevents and opposes pathogens. We could not translate the conclusions of an in vitro system with 3 components and 2 variables into an in vivo system with 3 components and 3 variables. They are not scientifically comparable and in vitro conclusions cannot be translated into in vivo systems to explain healing.
Thus, in the case of antibiotics that can eliminate the isolated bacteria in vitro, it cannot be said that the same antibiotic has an effect on the elimination of this pathogen or on the treatment of infection in vivo when it occurs in vivo. The only conclusions that can be drawn in this case are: the success of antimicrobial therapy in pathogen clearance and in vivo infection healing depends on the combined action of the antimicrobial drug and the immune system.
With the strong support of this view, the immune system is deficient in extreme age, functional disorders in the elderly and immature age. During this period of life, infections are often more severe and frequent, with higher morbidity and mortality, even when antibiotics are used with the correct indication, dosage and time.
Furthermore, in severe secondary immunodeficiency (such as terminal aids, end-stage tumor patients, other terminally immunocompromised patients and any type of primary immunodeficiency that is terminally severe) treatment with antibacterial drugs is not possible. In immunocompromised hosts, antibiotics are used at higher doses for the same clinical or veterinary setting than in immunocompromised patients. In underdeveloped areas where most people live, malnutrition affects the adaptability and functionality of the immune system.
The lack of sewage treatment systems and drinking water supplies expose these populations to a constant attack by a myriad of pathogens, compromising the efficiency of the defense system and causing disease. This constant challenge and frequent disease can create an unhealthy positive feedback cycle that continuously impairs the immune system and health. Finally, the lack of protection against environmental attack also weakens the body and immune system. These three cases, combined, also produce an unhealthy forward feedback loop in a coordinated manner. This severely damages the immune system, reduces the effectiveness of the antimicrobial drug, and shortens the life of these people. Without the cooperation of the immune system, no data is available to support the isolated effect of antibacterial drugs in vivo, since humans and animals cannot live without a functional immune system and upon invasion the immune system passes through an innate and adaptive response that ends only after clearance of the pathogen and after tissue repair and restoration of homeostasis (7, 8).
Consistent with this explanation, there is no clear evidence in the literature that a single action of an antibiotic or antibacterial drug can clear pathogens in vivo, and in conclusion, without a functional immune system, it is not possible to cure a serious antibacterial drug infection. In contrast, it is possible to cure certain infections without antibacterial drugs. Taken together, these evidences indicate a clear and important role exerted by the immune system in the cure achieved by antimicrobial drugs in vivo in infection (Reeves G, Todd i.characteristics on immunology. second edition: Blackwell Scientific Publications, 1991; Neto VA, nicotemo AC, Lopes hv.Antibi tica. second edition: Sarvier, 2007; Murray PR, Rosenthal KS, Pfaller ma.microbiology m. second edition: mostraby, 2006; bulsi LR, altthum f.microbiology. fifth edition: athenu Editora, 2008).
New explanations should be made to better understand the healing induced by antimicrobial drugs in vivo, without relying on the well-known in vitro antimicrobial mechanism of action. The inventors propose a new concept in which antimicrobial drugs can be considered as Equilibrium Shifters (ES) in host x-pathogen competition, which favors the host immune system in a multivariable environment. The variables include: concomitant diseases, trauma, age, sex, race, mental health, innate and adaptive immunity, metabolism, nutrition, physiological flora microbiota, environmental aggression by drugs, and exposure to radiation, gases, pathogens, and medical treatments.
It may happen that antibacterial drugs, through their action on bacteria, promote the role of the immune system in pathogen clearance, restore the host x pathogen balance competition and promote healing. The antimicrobial drug will act as a significant equilibrium displacer for host x pathogen competition: weakening the action of pathogens and reducing their number in vivo and in this way promoting the role of the immune system in microbial clearance. Other consequences are death or chronic infection, regardless of the antibacterial drug used.
Applying this new concept in the context of finding new therapies for severe or potentially incurable infection/inflammatory syndromes (such as sepsis or septic shock) deserves some consideration. Because the equilibrium displacer in the host is in equilibrium with the pathogen, the antibacterial drug has a mandatory partner of the immune system in vivo. By accepting this concept, antibacterial drugs are not the main players in achieving a cure, but are important and often necessary as accessory factors to help shift the balance favorable to the host, and in infectious/inflammatory diseases, a fundamental problem arises: how to modify and improve the established initial booster, ineffective, inappropriate adverse immune response, leading to an optimal, innate and adaptive Immune Response (IR) by the immune system, able to fight and eliminate pathogens, with a physiologically beneficial anti-inflammatory effect in the treatment of the disease.
Disclosure of Invention
Objects of the invention
In general, it is an object of the present invention to provide products comprising immunogenic compositions, in certain embodiments in combination with one or more antibiotics, and methods and uses for the treatment and/or prevention of infectious diseases and for the preparation of medicaments thereof.
It is a particular object of the present invention to provide an immunogenic composition for modulating the immune system comprising a therapeutically effective amount of two or more Immune Response Shifters (IRS) comprising an immunologically active antigenic agent exhibiting a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) and a stress response signal (1); and one or more physiologically acceptable carriers, excipients, diluents or solvents.
In particular, it is an object of the present invention to provide an immunogenic composition for modulating the immune system comprising an immune response displacer (IRS) with an immunologically active pathogen-associated molecular pattern (PAMP) and/or risk-associated molecular pattern (DAMP) and/or Stress Response Signal (SRS) selected from the group consisting of: A) an antigenic agent having a molecular pattern associated with bacteria; (B) an antigenic agent having a molecular pattern associated with a virus; (C) antigenic agents with molecular patterns related to fungi and yeast; (D) an antigenic agent having a molecular pattern associated with a protozoan; (E) an antigenic agent having a molecular pattern associated with multicellular parasites and/or (F) an antigenic agent having a molecular pattern associated with prions.
The invention also aims to provide the use of the above immunogenic composition for the preparation of a pharmaceutical product, as well as the use of a method for modulating the immune system, in particular for replacing in real time an ineffective immune response with an effective immune response.
It is therefore an object of the present invention to provide products and methods for the treatment of infectious diseases, including severe infections, sepsis and multiple resistant bacteria, as well as modulation of the immune system. The effectiveness of the present invention is attributed to the real-time replacement of ineffective immune responses with effective immune responses. This replacement is done by actively creating a new image (image) of the invading pathogen for the host immune system in order to reset, guide, control and improve it.
Replacing the ineffective immune response in real time to obtain a new effective immune response that can alter the host x pathogen balance competition, is a challenging task in providing the host with an opportunity to heal. This problem involves the Pasteur paradigm (Pasteur) which suggests that it is possible to immunize the host such that protection against invaders is conferred on the second encounter without significant clinical symptoms of the disease.
The basis of these phenomena is a defined immunological memory phenotype in T and B lymphocytes and lymphocytes, and to a lesser extent NK cells as recently demonstrated (7-21). In summary, these cells can induce an inflammatory intrinsic and adaptive response in the second contact with antigen. This is the basis for a prophylactic vaccine, which is the most effective drug created to date. Paradoxically, the prior art lacks a therapeutic vaccine against infectious diseases.
Reviewing the pasteur paradigm, we can model the two most effective prophylactic viral vaccines, smallpox and yellow fever (YF-17D), which were developed against invariant pathogens. The first eradication of smallpox until now, the second resulted in the development of protective immunity, which was sustained for more than 35 years after a single dose. A series of detailed modern scientific researches on YF-17D yellow fever vaccines by using a system biology and system vaccinology method prove that the virus can contact with inherent cells of a wide range of sentries and professional APC to activate the same cells. Multiple DC subsets are activated per DC cell type and subset as well as in multiple subsets and DC cell types as well as other APC and NK cells by stimulation of multiple PRRs, DRRs, by multiple PAMP and DAMP stress receptors, stress signals.
These multiple sentry cell activations lead to complex and multiple coordinated DC activations in multiple inflammatory and lymphoid regions leading to systemic CD4 TH1, CD4 TH2, CTL CD8 and B cell and antibody polyclonal responses that eliminate and inactivate viremia. The clearance of viruses and infected cells renders them unrecoverable and permanent in the environment (42).
Some immune system malfunctions due to rare genetic defects may lead to a rare vaccine disease, often very severe or even fatal, further demonstrating that vaccine virus elimination is a problem in the favorably-induced disease between the host immune system and the virus rather than single vaccine immune competition (43). The background of activation of systemic subclinical disease is enormous and completely different from single repeat immunizations with antigen vaccines, which is one of the reasons for the high efficiency of these two vaccines (1) (44-50).
In summary, aggressive wild-type viruses affect the host-pathogen balance in a manner different from vaccine viruses, resulting in severe disease in one patient and subclinical disease in another (1) (44-50). It is well known that overlapping acute infections, such as cancer or chronic infections, of chronic diseases can induce a cure of the underlying disease (42, 51). Potent activation may outperform ineffective activation, resulting in a balanced competition and ultimately improved outcome by an altered host x pathogen (42, 51). It is well known that activation induced by an effective overlap of unrelated specific immune responses is the best known way to rescue a tolerizing, immunosuppressive or non-reactive state to a normal reactive state (52).
In the same way, experiments with mutagenic transformation of low to highly immunogenic tumours induced tumour rejection, which could not be produced with wild tumours, and also induced CTLs against subdominant epitopes (53, 54). PAMPs alone can remodel lymph node feed arterioles and induce lymph node hypertrophy, which is essential for an effective primary adaptive response. Unrelated activated or primed effector memory T-specific CD4+ CD40L + elicits autoimmune diseases or ameliorates immune responses in persistent infections or neoplastic diseases by HEV and allowing dendritic cells to migrate to T cells in a CD62P-dependent manner (4,52, 55). Effector memory CD 8T cells released CCL3, which in turn activated MPCs to produce TNF α that induced PMNN and other MPCs to produce ROIs and clear bacteria. Unrelated pathogens susceptible to ROI were also cleared by alternative activation (6, 56-59). Recently, it has also been recognized that the status of the microbiome of the gut flora intervenes and can determine the effectiveness of a given vaccination.
These conditions of disease and vaccine disease, isolated disease and overlapping disease were studied in parallel, blocking specific immune responses overlapping with effective specific immune responses, natural non-immunogenic and mutagenic tumours, vaccine immunity and persistent immune responses to microbiome flora and T CD4 effector memory cells and CD 8T effector memory inducing potent activation of innate cells, the effect of PAMPs on fed lymph node arterioles and lymph node hypertrophy and other studies described above, and other studies revealed that the point at which immune responses that should be considered in the pasteur paradigm are very important is the proposition of new working hypotheses aimed at improving the treatment of infection/inflammation, tumours, allergies and other diseases in the context of new therapeutic design.
These important observation points are:
the 1-immune system is reactive rather than active, it has a unique huge response potential, but only with stimulated linkages, they find invaders in the context of host x parasite competition balances. Thus, the outcome of a given new immune response is always somewhat an occasional return determined by the host x parasite competition balance, which, if effective, is not the best response. In conclusion, the primary immune response is always an accidental response that may be left to improve.
2-the best possible response or protection occurs only in secondary reactions due to effective memory formation after effective vaccination cure for severe disease. Thus, memory cells are critical for the generation of protective immunity.
The 3-intrinsic response itself is not specific and it is possible to maintain multiple specific adaptive responses with synergistic or antagonistic effects at the same time and in the same region. Since human and animal organisms can remain multiply invasive simultaneously, even in the same region, the pool of innate immune receptor recognition systems can recognize an expanded and variable range of PAMPs, DAMPs and stress signals, rather than a limited recognition to recognize the identity of the invading pathogen through adaptive immunity.
4-based on the above features and studies of YF-17D vaccine induced protection mechanisms, the logical logic to effectively activate innate immunity contradicts that DRR and stress signals must be based on the multiplicity and diversity of activation of PRRs in different hosts, with multiple cytokine and chemokine secretion in multiple regional lymphomas and no lymphomas in different cellular compartments and multiple cell sentry and APC cell types to achieve the best available adaptive immune response, independent of the range of antigen receptors being activated in the adaptive specific response.
The primary role of the 5-primary response is to limit the pathogen in the pro-inflammatory setting until a potent adaptive response occurs. The primary adaptive response to acute infection is also pro-inflammatory. Both can be very harmful if the contact surface is large and often causes symptomatic disease and may also induce harmful fatal systemic inflammation.
6-Secondary innate and adaptive potent responses are provided by T, B memory cells, and in some cases NK memory cells, which when available provide faster, correctly polarized, more accurate, quiet, low inflammation, and protective immune responses. These improved secondary adaptive immune responses have to remember cells due to their anti-inflammatory properties and can effectively address a wide range of pathogen surface contacts throughout the body without harm to the human and animal organism.
7-in the overlapping cases cited above, activation of the intrinsic areas of both diseases for the same cellular sentry, APC, with release of common cytokines, common chemokines, is an immune response and the overall context of fighting, which will be in the same activated lymph node and inflammatory area, will be the same for both responses. When secondary and primary adaptive responses occur simultaneously, the secondary adaptive immune response is the primary immune response through the action of memory cells, which resets signaling in both innate and adaptive cells and induces a primary response that transitions to a low inflammatory pattern in modified regions of target memory.
In addition, these effects can be achieved by injecting a mixture of PAMPs and secondary antigens to recognize memory cells that induce secondary immune responses and optimally activate PMCs and PMNNs to clear bacteria sensitive to ROI and other mechanisms and optimally activate lymph nodes and improve ongoing immune responses or can induce poor or tolerant or non-immunogenic induction.
In summary, the immune system is reactive rather than active, and the quality and effectiveness of the innate immune response is largely dependent on two factors:
the first factor is the presence or absence of immunologically effective specific memory, which determines the secondary or primary immune response. In case of secondary responses, an optimal response can be obtained, the result being silence protection. In the case of primary responses, new immune responses are always occasionally responded, and the results depend on secondary factors and can be improved.
The second factor is the host x parasite competition balance (40, 49, 53,54, 60-78).
Thus, the immune system itself cannot ameliorate an existing primary immune response, and the answer to the question of how to alter and ameliorate an existing inappropriate primary immune response is clearly complex but strategically simple, as only two factors determine the outcome. In primary immune responses, only one remaining factor is the background for the competitive balance of host x pathogens, and modifications are needed to improve ongoing inefficient immune responses. The antimicrobial drug acts by weakening, pathogen action and reducing its in vivo number, and as described and suggested above will act as host x pathogen competing ES. By this action, the antimicrobial drug can correctly alter the host pathogen balance and outcome, but does not alter the nature of the ongoing primary response. After such rational analysis, it is sufficient to change the nature of the ongoing primary inappropriate innate immune response to secondary effective criteria in favor of the organism. Obviously, the immune system cannot accomplish this without assistance, since it estimates a longitudinal delay through the differentiation step. How to switch in real time, is the primary incidental response immediately in the best possible response to the secondary? The answer is as much secondary activation as possible.
To accomplish this task, the strict response characteristics of the immune system in primary response are mainly dependent on the immunogenicity and role of the pathogen and the adaptability of the immune system, opening the door for active medical immune interventions that can be fully used by all people. The enormous immunological potential of the remaining available responses alters the host x parasite competition balance, favoring the subject with a new secondary standard for this initial IR. This strategic and planned immune action must be able to reset, direct, control, modify and improve the action of the immune system in real time to induce favorable secondary specific effective IR, thereby positively altering the background of host x parasite competition and outcome.
The only possible answer is to change perception or how the immune system treats and characterizes the invading substance by including a large and diverse number of new secondary memory epitopes that build new perception identities for the invading pathogen.
This new perceptual identity can be established in controlled periods in all lymphatic sites or even in inflammatory areas of the disease, which naturally completely alters the secondary massive activation. Now, with a new optimal secondary activation of the ongoing disease, the immune system can reprogram the immune response, mainly based on secondary well-known antigenic determinants, a few of which are from invasive pathogens, which will generate a completely new and different effective specificity and well polarized immune response. In secondary resetting, low inflammation areas, the best possible secondary tract will be produced.
The sum of the total effective anti-inflammatory secondary responses to newly generated images of invasive pathogens can restore all induced tolerance, anergy, escape mechanisms, and can also induce immune responses to all weak antigens or subdominant epitopes to produce the best possible effective response in completely different poor inflammatory battlefields, creating a completely new host x parasite competition balance, which is favorable to the host. To achieve this goal, it is necessary to create a new ES balance shifter and IRS (immune response shifter), the role and creation of which should be based on the important and obvious observations in the above detailed pasteur-paradigm study.
This new IRS for the active role of proposed and planned immunotherapy must consist of a wide diverse range of pathogen secondary antigens for which the organism configures an effective memory pool. These antigens must be preferentially inert and should be used in all areas of disease beyond their limits.
Such antigens should be able to induce a variety of large secondary anti-inflammatory activations, completely overlapping pathogen-induced primary pro-inflammatory activations. These antigens should be applied every 3 to 5 days to suppress the production of immunosuppressive cells that mimic the withdrawal of disease. The proposal for this immunotherapy is to create a new virtual but real foreign endogenous pathogen at the biological level, which is fully recognized by innate and adaptive immunity and in most cases secondary and well-known aggressiveness by memory-effective cells, thereby inducing the best available immune response to replace the primary immune response. Changing the internal image of pathogens taken up by both innate and adaptive memory cells, we can now actively change the host x environment of pathogen competition in a manner that is favorable to the host. The reactive immune system, which is activated excellently by active immunotherapy, will reprogram in real time, reset and guide the best available secondary anti-inflammatory specific immune response against the pathogen, thus restoring its primary dominance in the ongoing disease.
To demonstrate that the new perception images of the innovative IRS against exogenous or endogenous pathogens can be controlled in real time, by the concept of resetting and leading to established pathological responses, we used some paradoxical cases involving lethal, irreversible sepsis, mainly multi-resistant microorganisms, beyond the range of the best available antibiotics used in combination.
The following positive significant results of this clinical case shown in the examples demonstrate and demonstrate that by replacing, treating and modulating the immune system during disease treatment, the immune system can be controlled, reset, directed and generate new secondary effective anti-inflammatory immune responses in real time. The primary immune response, which is harmful to the host, is initially amplified, ineffective, inappropriate by actively creating new images of aggressive pathogens.
This is the first demonstration that it is possible to control, reset and direct an ongoing immune response in vivo, thereby favoring the host, thereby positively altering the host's competitive balance of x pathogens and outcome, and also having a drug with significant synergy with the antibacterial agent.
Another object of the invention is the use of the immunogenic composition for the prevention and/or treatment of infectious diseases. In particular, methods of treating bacterial infections and sepsis are provided, as well as the use of the above immunogenic compositions in the manufacture of medicaments and kits for treating bacterial infections.
Definition of
In the description of the present patent application, abbreviations are used several times, and their definitions are summarized below according to their usage in the present application:
IRS: immune response shifter
BCG refers to attenuated Mycobacterium bovis, BCG;
DAMP refers to a risk-associated molecular pattern;
DECA refers to IRS composition 1a described in example 1 of the present patent application;
GM-CSF refers to "granulocyte macrophage colony stimulating factor";
PAMP refers to pathogen-associated molecular patterns.
PFU: plaque forming units.
PPD refers to a purified protein derivative of M.tuberculosis;
PPD refers to the fraction of the purified protein extract culture of Koch's bacillus ("purified protein derivative"). PPD is the major antigen of mycobacterium tuberculosis;
TDCI50 is the unit used to quantify viral particles, the infectious dose at which 50% of the cells in tissue culture are infected;
corynebacterium crenatum refers to inactivated mycobacterium bovis lysate;
the unit Lf or "floc flocculation units" is an international unit accepted by the world health organization for quantification of antigens in toxoid vaccines;
VITER: IRS composition 1b described in example 1.
ISR: integrated stress response
SRS: stress response signal
SRR: stress response receptor
ES: balanced shifter
Drawings
The following drawings are part of the present report and are included to demonstrate certain aspects of the present invention. The objects of the invention may be better understood by reference to one or more of these drawings in combination with the detailed description of the preferred embodiments presented herein.
Figure 1 shows the image of example 2. A1, A3, and a4 show the wounds following surgical debridement of day 29/1 year 2011. It may be found that sepsis-associated multiple lesions resulting from multiple resistant strains and major tissue loss continue to perform poorly, having a general appearance of granulation tissue without any healthy appearance. The X-ray identification of external fixation of the femur after surgery was made on 29/1/2011 (a 2). On day 2/2 (5 days after treatment initiation) 2011, patients were completely recovered from sepsis and received ICU discharge (B1, B2, and B3). In B1-B3, healthy granulation tissue characteristics of the second healing process may be identified. In C1 (3/1/2011), the improvement in leg damage described in a1-a4 was evident, for which reason patients were discharged on 3/15/2011. At D1 (central site) and D2 (lateral site) it was possible to verify the complete recovery of the multiple wound complex wound associated with multiple resistant acinetobacter and severe sepsis caused by osteomyelitis. These data strongly suggest that the decisive role of DECA immunotherapy in relation to debridement and antibiotics heals clinical conditions in a relatively short time, so that patients can not only survive natural unleasure, but also walk again without crutches or walking sticks.
Fig. 2 shows an image of example 3. Following immunotherapy in CMS patients, breast CT scans (a1 and a2) were performed 11 months and 1 days 2011 before immunotherapy and 2011 CT scans 11 months and 4 days (B1 and B2). White areas (circles) characteristic of infection can be identified in a1 and a 2. The disappearance of the white area and the restoration of the lung parenchyma (the image thereof becomes darker) are clearly visible in B1 and B2. These data show that immunotherapy combined with antibacterial treatment can cure aspiration pneumonia.
Fig. 3 shows an image of example 4. X-rays (a1) from CT scans at 24 days 4/2007 (3 days after initiation of immunotherapy) and 27 days 4/2007 (B1 to B6) readily identified severe SARS conditions in septic shock. X-ray at 6 days 5-2007 (C1) demonstrated complete recovery after immunotherapy in AMB patients. In a1, white areas (circles) characteristic of infection can be identified. In B1-B6, where the clinical status is very important, the white areas barely identify the anatomical contours of our parameters (circles). In C1, the disappearance of the white areas and the complete restoration of the lung parenchyma were clear, with no sequelae, and the image became darker. These data show that sepsis associated with SARS, CIVD, liver and kidney failure can be cured within 15 days in combination with 6 courses of immunotherapy and antimicrobial therapy.
Detailed Description
In a first embodiment, the invention relates to a pharmaceutical product comprising one or more antibiotics and one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more (e.g., 3, 4,5, 6,7, 8,9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 or more) synthetic or natural antigenic agents or parts and combinations thereof, and one or more physiologically acceptable carriers, excipients, diluents or solvents, said synthetic or natural antigenic agents comprising pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) selected from at least two of the group consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
Such pharmaceutical products may be compositions, kits, medical devices, or any other product intended to deliver an antibiotic and one or more immunogenic compositions as described above to a tissue.
The one or more antibiotics comprised in the pharmaceutical product of the invention may be selected from the following categories: amino acid derivatives, aminoglycosides, aureomycins, aziridines, ansamycins, benzenes, benzimidazoles, carbapenems, cephalosporins, coumarin-glycosides, diphenyl ether derivatives, diketopiperazines, fatty acid derivatives, glucosamine, glycopeptides, imidazoles, indole derivatives, lipopeptides, macrocyclic lactams, macrolides, nucleosides, penicillins and cephalosporins (β -lactams), peptides, peptidyl nucleosides, chloramphenicol, polyenes, polyethers, pyridines and pyrimidines, quinolones and fluoroquinolones, statins, steroids, sulfonamides, taxol and tetracyclines.
Preferably, the immunogenic composition of the invention comprises an immunologically active antigenic agent exhibiting a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) selected from the group consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with multicellular parasites, and (F) an antigenic agent having a molecular pattern associated with prions.
More preferably, the composition of the invention comprises at least 3 classes of pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) selected from (a), (B), (C), (D), (E) and (F) above.
More preferably, the composition of the invention comprises at least 4 classes of pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) selected from (a), (B), (C), (D), (E) and (F) above.
The antigenic agent of the invention may be selected from epitopes, genetic material, lipids, polysaccharides and/or immunologically active proteins of the invention, obtainable by purification from isolated fragments of naturally occurring materials or fractions derived from plant, animal or microbial extracts, or produced by genetic recombination, preferably from viral, fungal, parasitic or bacterial prion strains.
Thus, the antigenic agent of the invention having a molecular pattern associated with the bacterium of the invention is selected from, but not limited to, antigenic agents having a molecular pattern associated with a bacterium of the genus: staphylococcus (Staphylococcus), Streptococcus (Streptococcus), Enterococcus (Enterococcus), Corynebacterium (Corynebacterium), Bacillus (Bacillus), Listeria (Listeria), Clostridium (Clostridium), Mycobacterium (Mycobacterium), Actinomyces (Actinomyces), Nocardia (Nocardia), Escherichia (Escherichia), Proteus (Proteus), Klebsiella (Klebsiella), Serratia (Serratia), Enterobacter (Enterobacter), Salmonella (Salmonella), Shigella (Shigella), Pseudomonas (Pseudomonas), Burkholderia (Burkhkderia), Thermomyces (nontrophonas), Stenolobacter (Acinetobacter), Neisseria (Vibrio), Campylobacter (Campylobacter), Campylobacter (Pseudomonas), Haemobacter (Halobacter), Haemophilus (Pseudomonas), Haemophilus), Corynebacterium (Salmonella), Corynebacterium (Corynebacterium), Mycobacterium (Corynebacterium), Mycobacterium (Corynebacterium) and Mycobacterium (Corynebacterium) are used for the genus (Corynebacterium), Bacillus (Corynebacterium) and Bacillus (Corynebacterium) can be strain (Corynebacterium), Bacillus (Corynebacterium) can be (Corynebacterium), Bacillus (Corynebacterium) can, Corynebacterium (, Francisella (Francisella), Pasteurella (Pasteurella), Yersinia (Yersinia), Legionella (Legionella), Gardnerella (Gardnerella), Treponema (Treponema), Leptospira (Leptospira), Borrelia (Borrelia), Mycoplasma (Mycoplasma), Rickettsia (Rickettsi) and Chlamydia (Chlamydia).
Antigenic agents having a molecular pattern associated with the viruses of the present invention may be selected from, but are not limited to, antigenic agents having a molecular pattern associated with the following virus families: adenoviridae, arenaviridae, bunyaviridae, coronaviridae, filoviridae, flaviviridae, hepadnaviridae, delta hepadnaviridae, caliciviridae, herpesviridae, orthomyxoviridae, papovaviridae, paramyxoviridae, parvoviridae, picornaviridae, papovaviridae, reoviridae, retroviridae, rhabdoviridae, and togaviridae.
Antigenic agents having a molecular pattern associated with the fungi and yeasts of the invention may be selected from, but are not limited to, antigenic agents having a molecular pattern associated with fungi and yeasts of the genera: sporomyces (Sporothrix), Aspergillus (Aspergillus), Blastomyces (Blastomyces), Candida (Candida), Coccidioides (coccoides), Cryptococcus (Cryptococcus), Histoplasma (Histoplasma), and Pneumocystis (Pneumocystis).
The antigenic agent having a molecular pattern associated with a protozoan of the present invention may be selected from, but is not limited to, antigenic agents having a molecular pattern associated with a protozoan of the genus: cryptosporidium, Cyclosporidium, Enamantaria, Glabra, Giardia, Leishmania, Plasmodium, Toxoplasma, Trichomonas, Trypanosoma, Microsporidium and Isospora.
The antigenic agents with molecular patterns associated with the multicellular parasites of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with the multicellular parasites trematodes, cestodes and nematodes.
The antigenic agents of the present invention include proteins, polysaccharides, lipid molecules and/or complex synthetic molecules that mimic proteins, polysaccharides and/or lipid molecules.
More specifically, the agents of the invention include immunologically active antigenic protein molecules having enzymatic activity, such as kinases, phosphatases, streptokinases (streptokinases), streptococcal dnases (estreptodernases) and deoxyribonucleases (e.g. streptodornases).
The immunogenic composition for modulating the immune system of the present invention comprises 0.001 to 500 micrograms/ml of each immunogenic agent.
Such immunogenic agents may be enclosed in capsules, microparticles, nanoparticles, coated tablets, liposomes.
In particular, the immunogenic composition for modulating the immune system of the invention comprises between 4 and 20 antigenic agents selected from the group consisting of agents: streptococci, levedorin, Candida, PPD, prions, streptokinase (streptokinase), streptococci toxoid, diphtheria toxoid, tetanus toxoid, tubercle tuberculin (Koch' stubergilin), inactivated ascaris hominis lysate, certain species of Aspergillus, Aspergillus flavus (Aspergillus flavus), Aspergillus fumigatus (Aspergillus fumigatus), Aspergillus terreus (Aspergillus terreus), certain species of Candida (Candida), Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Candida parapsilosis, certain species of Chlamydia (Chlamydia), Chlamydia pneumoniae (Chlamydia pneumoniae), Chlamydia parvus (Chlamydia), Chlamydia pneumoniae (Chlamydia pneumoniae), Chlamydia sp (Chlamydia trachomatis), Chlamydia trachomatis (Chlamydia), Chlamydia sp (Chlamydia sp), trichotheca (Chlamydia sp), enterobacter sphaera (Chlamydia sp), enterobacter neospora (enterobacter sphaeromonas), enterobacter sphaeromonas (enterobacter sphaericus), enterobacter sphaericus (enterobacter sphaerobacter sphaericus), enterobacter sphaericus (enterobacter sphaerotheca), enterobacter sphaerotheca (enterobacter sphaerothecoides), enterobacter sphaerotheca (enterobacter sphaerotheca), enterobacter sphaerotheca (enterobacter sphaerochlamy), enterobacter sphaerotheca (enterobacter sphaerotheca), enterobacter sphaerochlinoculus (enterobacter spha, Giardia lamblia (Giardia lamblia), Haemophilus influenzae (Haemophilus influenzae), Microsporum canis (Microspora-cannis), certain species of Mycobacterium (Mycobacterium), Mycobacterium bovis, Mycobacterium leprae (Mycobacterium leprae), Mycobacterium tuberculosis, Neisseria gonorrhoeae (Neisseria gonorrhoeae), human papilloma virus, poliovirus, certain species of Proteus (Proteus), Proteus mirabilis (Proteus mirabilis), Proteus pengii (Proteus penerii), Proteus vulgaris (Proteus vulgaris), certain species of Salmonella (monella), Salmonella gordonella (Salmonella bongori), Salmonella enteritidis (Salmonella enterica), certain species of Serratia, Shigella (Salmonella choleraesula), Shigella (Shigella flexnerii), Shigella (Shigella flexnerella), Shigella (Shigella) and Shigella (Shigella) strains, Staphylococcus aureus (Staphylococcus aureus), Staphylococcus epidermidis (Staphylococcus epidermidis), Strongyloides stercoralis (Strongyloides stercoralis), Streptococcus (Streptococcus), Streptococcus bovis (Streptococcus bovis), Streptococcus viridis (Streptococcus viridis), Streptococcus equina (Streptococcus equinus), Streptococcus pneumoniae, Streptococcus pyogenes (Streptococcus pygene), Toxoplasma gondii (Toxoplasma gondii), Trichostoma vaginalis (Trichomonas vaginalis), Trichophyton, certain species of the genus Trichophyton (Trichophyton), Trichophyton rubrum (Trichophyton rubrum), Trichophyton (trichophytons), Trichophyton mentagrophytes (trichophytons), yellow fever virus, hepatitis b virus, rubella virus, varicella zoster virus, variola virus, mumps virus, measles virus, herpes virus, and vaccinia virus, or synthetic analogs that exhibit pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) associated with such antigenic agents.
In various embodiments, the immunogenic composition for modulating the immune system of the invention comprises 4,5, 6,7, 8,9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19 or 20 antigenic agents selected from the group consisting of antigens derived from: streptococci, levedorin, Candida, PPD, prions, streptokinase (streptokinase), streptococci toxoid, diphtheria toxoid, tetanus toxoid, tubercle tuberculin (Koch's tuboculin), inactivated ascaris hominis lysate, certain species of Aspergillus, Aspergillus flavus (Aspergillus flavus), Aspergillus fumigatus (Aspergillus fumigatus), Aspergillus terreus (Aspergillus terreus), certain species of Candida (Candida), Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Candida parapsilosis, certain species of Chlamydia (Chlamydia), Chlamydia pneumoniae (Chlamydia pneumoniae), Chlamydia parvum (Chlamydia), Chlamydia sp (Chlamydia psidii), Chlamydia oculata (Chlamydia trachomatis), Chlamydia sporotrichum (Chlamydia), enterobacter sphaericus (Chlamydia sp), enterobacter sphaerophilus (Chlamydia sp), enterobacter sphaera (enterobacter sphaerothecoides), enterobacter sphaera (enterobacter sphaerobacter sphaerothecoides), enterobacter sphaera (enterobacter sphaera), enterobacter sphaerothecoides (enterobacter sphaerothecoides), enterobacter sphaerothecoides (enterobacter sphaera), enterobacter sphaerothecoides (enterobacter sphaerochlamycolchicum), enterobacter sphaerae (enterobacter sphaeroides (enterobacter sphaerae), enterobacter sphaerae (enterobacter sphaerothecoides), enterobacter sphaerae (enterobacter sphaerochaete, Giardia lamblia (Giardia lamblia), Haemophilus influenzae (Haemophilus influenzae), Microsporum canis (Microspora-cannis), certain species of Mycobacterium (Mycobacterium), Mycobacterium bovis, Mycobacterium leprae (Mycobacterium leprae), Mycobacterium tuberculosis, Neisseria gonorrhoeae (Neisseria gonorrhoeae), human papilloma virus, poliovirus, certain species of Proteus (Proteus), Proteus mirabilis (Proteus mirabilis), Proteus pengii (Proteus penerii), Proteus vulgaris (Proteus vulgaris), certain species of Salmonella (monella), Salmonella (Salmonella bongori), Salmonella enteritidis (Salmonella enterica), certain species of Serratia, Shigella (Serratia), Shigella (Shigella flexneri), Shigella (Shigella inflexella (Shigella), Shigella (Shigella) and Shigella (Shigella) strains, Staphylococcus aureus (Staphylococcus aureus), Staphylococcus epidermidis (Staphylococcus epidermidis), Strongyloides stercoralis (Strongyloides stercoralis), Streptococcus (Streptococcus), Streptococcus bovis (Streptococcus bovis), Streptococcus viridis (Streptococcus viridis), Streptococcus equina (Streptococcus equinus), Streptococcus pneumoniae, Streptococcus pyogenes (Streptococcus pygene), Toxoplasma gondii (Toxoplasma gondii), Trichostoma vaginalis (Trichomonas vaginalis), Trichophyton, certain species of the genus Trichophyton (Trichophyton), Trichophyton rubrum (Trichophyton rubrum), Trichophyton (trichophytons), Trichophyton mentagrophytes (trichophytons), yellow fever virus, hepatitis b virus, rubella virus, varicella zoster virus, variola virus, mumps virus, measles virus, herpes virus, and vaccinia virus, or synthetic analogs that exhibit pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) associated with such antigenic agents.
Preferred immunogenic compositions of the invention comprise inactivated M.bovis lysate, purified protein derivatives of M.tuberculosis, inactivated Staphylococcus aureus (Staphylococcus aureus) lysate, inactivated Staphylococcus epidermidis lysate, inactivated pyogenic lysate, inactivated Streptococcus pneumoniae (Streptococcus pneumoniae) lysate c inactivated enterococcus faecalis lysate, streptokinase/streptodornase, inactivated Candida albicans (Candida albicans) lysate, inactivated Candida glabrata (Candida glabrata) lysate, inactivated Trichophyton floccosum (Epidermophyton floccosum) lysate, inactivated Microsporum canis lysate, inactivated Trichophyton mentagrophytes (Trichophyton mentagrophytes) lysate, inactivated Escherichia coli (enteropathogenic Escherichia coli) lysate, inactivated Salmonella bangolensis (Salmonella bongori) lysate, inactivated Salmonella enterica (Salmonella enterica) lysate, and inactivated Salmonella subterranean lysate.
Preferred immunogenic compositions of the invention comprise from 0.001 to 1ng/ml of inactivated M.bovis lysate, from 0.001 to 1ng/ml of purified protein derivative of M.tuberculosis, from 0.1 to 100. mu.g/ml of inactivated S.aureus lysate, from 0.1 to 100. mu.g/ml of inactivated S.epidermidis lysate; 0.1 to 100. mu.g/ml of an inactivated Streptococcus pyogenes (Steptococcus pyogenes) lysate; 0.1 to 100 μ g/ml of inactivated streptococcus pneumoniae lysate; 0.1 to 100 μ g/ml of inactivated enterococcus faecalis lysate, 0.01 to 10 μ g/ml of streptokinase, 0.01 to 10 μ g/ml of streptococcal enzyme; 0.1 to 100 μ g/ml of inactivated candida albicans lysate; 0.1 to 100 μ g/ml of inactivated Candida glabrata lysate, 0.1 to 100 μ g/ml of inactivated Trichophyton floccosum lysate; 0.1 to 100 μ g/ml of inactivated microsporum canis lysate, 0.1 to 100 μ g/ml of inactivated trichophyton mentagrophytes interdigital variant lysate; 0.1 to 100 μ g/ml of an inactivated enteropathogenic escherichia coli lysate; 0.1 to 100 μ g/ml of an inactivated Salmonella poinggorensis lysate, 0.1 to 100 μ g/ml of an inactivated Salmonella enterica lysate, and 0.1 to 100 μ g/ml of an inactivated Salmonella underground lysate.
The compositions of the invention may also contain excipients such as bactericides, bacteriostats, antioxidants, preservatives, buffers, stabilizers, pH adjusting agents, osmolality adjusting agents, antifoams and surfactants as well as residual antigen inactivating or fractionation agents, growth medium components and solvents commonly used in the production of vaccines and immunotherapy.
The compositions of the present invention may be solid, liquid or gel. As used herein, the use of the term "pharmaceutically acceptable carrier" means a non-toxic solid, an inert semi-solid liquid excipient, a diluent, any type of auxiliary formulation, or simply a sterile aqueous solution, such as saline. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose, starches such as corn starch and potato solution, cellulose and its derivatives such as carboxymethyl cellulose, ethyl cellulose and cellulose acetate, cyclodextrins; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, polyols such as glycerol, sorbitol, mannitol and polyvinyl esters (polyethyleenters) such as ethyl laurate, ethyl oleate, agar, buffers such as aluminum hydroxide and magnesium hydroxide, alginic acid, pyrogen-free water, isotonic saline (isotonic saline), Ringer's solution, buffered solutions of ethanol and phosphate, and other non-toxic compatible substances for pharmaceutical formulation.
Multiple routes of administration for animals or humans for the immunotherapeutic compositions and vaccines described herein are available. The particular mode selected will depend upon the antigenic agent selected, the dosage required for therapeutic efficacy, and the patient to whom the composition is administered. The methods of the invention can generally be performed using any mode of administration that is biologically acceptable (i.e., any method that produces an effective level of immune response without eliciting a clinically harmful response). Such modes of administration include intradermal, oral, rectal, sublingual, topical, nasal, transdermal, or parenteral administration. The term "parenteral" includes subcutaneous, intravenous, epidural, irrigation (irrisation), intramuscular, release pump (release pump) or infusion. In particular, in the present invention, oral, intradermal, parenteral, subcutaneous, intravenous, intramuscular, and nasal mucosal and/or oral administration are preferred for administration of the compositions claimed herein.
For parenteral administration, the active ingredient may also be dissolved in a pharmaceutical carrier and administered in the form of a solvent, emulsion (including microemulsions and nanoemulsions) or suspension. Examples of suitable carriers are water, saline, dextrose solution, fructose solution or animal, vegetable or synthetic origin oils. Other vehicles may also contain other ingredients such as preservatives, suspending agents, solubilizers, buffers, and the like.
In a second embodiment, the invention relates to a method of treating sepsis in a human or animal with a bacterial infection, the method comprising administering to the human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions to modulate the immune system. The immunogenic composition comprises a therapeutically effective amount of three or more (e.g., 3, 4,5, 6,7, 8,9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 or more) synthetic or natural antigenic agents, or portions and combinations thereof, comprising pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) of at least two groups selected from the group consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
Sepsis is defined as an extremely severe infection in which one or more bacteria or microorganisms enter the blood from their entry point and begin to circulate in enormous numbers, gaining the establishment of colonized tissues, organs, and in the most severe cases, successfully reaching the surface of the majority of the body. Generally, when the microbial load is too great, a large number of bacteria and their toxic and metabolic products, as well as an immense number of PAMPS and DAMPS, come into contact with all, and an immense number of PRRs and RDPs on most body surfaces, producing a broad, powerful and acute general inflammatory process with a large release of cytokines from all these signs (cytokine storm).
The adverse progression of sepsis is caused by massive release of pro-inflammatory cytokines such as TNF, IL1, IL18, IL6, etc., causing inflammatory collapse (inflimatoromelapse) with hemodynamic characteristics altered such as hypotension, rapid pulse, which culminates in septic shock, which is generally irreversible. Sepsis, sepsis is a serious infection with high morbidity and mortality. In such severe infections, the immune system begins to act to eliminate bacteria at any cost in response to its impaired surgical potential due to bacterially-induced weakness and retardation, disproportionately increasing inflammation through the inflammatory Th17 tissue profile, thereby damaging the organism. (33)
In this inflammatory tissue profile, the effector loop of innate immunity controlled by TCD4 lymphocytes causes tissue damage, sometimes major destruction, which damages organs and tissues and exacerbates infection, leading to e.g. respiratory failure, lung shock, and in ARDS (adult respiratory distress syndrome) also to renal failure and multiple organ failure.
Thus, in sepsis, sepsis and septic shock, there are two variables that should be considered strategically and should be targets for immunotherapy so that it can be successful. These two variables are inflammation caused by the massive spread of countless bacteria throughout the body and their binding to PRR and DPP and stress signals in DC and sentry cells and polarization of the Th17 profile due to the functional infeasibility of the Th1 and Th2 profiles. These variables are the cornerstone of the severity, morbidity, and mortality of these diseases.
By considering these two variables, in order for immunotherapy to be effective in these infections, it should be used to cover the entire body surface, including the maximum number of lymphatic regions that geographically overlap with the effects of the pathogen. It should also be used in the damaged area and the area surrounding the damage so that they can restore the integrity of the T-loop by its action together causing extensive background reconstruction and producing a broad, extensive and strong anti-inflammatory effect by effector/memory T-cells produced in the application site. It should polarize the Th17 inflammatory tissue profile in parallel towards the TCD4 response of the bodily fluid Th2 and cellular Th1 profiles through the above background reconstruction and reprogramming, further reducing cells in the systemic inflammatory body through the action of memory cells can eliminate physiologically huge inflammation.
If the circular expansion using IL2 should be very low, the immune response, which is just sufficient to specifically amplify the inflammatory profile, repolarizes the immune profile or Treg/TRI regulatory profile.
Thus, by immunotherapy using the composition of the invention, the direction of the immune response will be altered by background reconstruction and reprogramming by overlaying immune cells (by anti-inflammatory action of unrelated specific memory T lymphocytes), by repolarization of the tissue inflammation profile TH17 to the selected potent TH1 and TH2 immune profiles. This immune response, which is renewed in real time during infection, in combination with a biological equilibrium displacer, in the case of the use of different antimicrobial agents, has the opportunity to be extremely beneficial to the microorganisms therein, reverse the microorganisms at the end of the favorable curve for the host, and have the opportunity to resolve.
The adequacy of this protocol to the pathology and "state" of the immune system of the patient to be treated.
In the case of sepsis and sepsis, the integrity and functionality of the T-loop is not sufficient to polarize, by its own pathophysiological mechanisms, the inhibitory TREG profile in cancer and the Th17 profile for inflammatory tissue in sepsis (whose immune system is attacked by the disease and is almost completely inoperable). In these cases, as in the examples cited herein, the background reconstitution must reach the whole body to reverse all symptom-induced immunosuppression, tolerance and immunological neglect, as well as to restore all the surgical and functional capabilities of the immune system to have an effective immune response that is reprogrammed and renewed.
In a third embodiment, the invention relates to a method of treating a multiple resistant bacterial infection in a human or animal suffering from a bacterial infection, the method comprising administering to the human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions for modulating the immune system, the immunogenic composition comprises a therapeutically effective amount of three or more (e.g., 3, 4,5, 6,7, 8,9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 or more) synthetic or natural antigenic agents, or portions and combinations thereof, and one or more physiologically acceptable carriers, excipients, diluents or solvents, the synthetic or natural antigenic agent comprising pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) selected from at least two of the group consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
In a fourth embodiment, the invention relates to a method of modulating the immune system response in a human or animal having a bacterial infection, the method comprising administering to the human or animal an effective amount of one or more immunogenic compositions comprising a therapeutically effective amount of three or more (e.g., 3, 4,5, 6,7, 8,9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 or more) synthetic or natural antigenic agents, or parts and combinations thereof, comprising pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) selected from at least two of the group consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
In other aspects, the invention relates to the use of immunogenic compositions for the preparation of medicaments and kits for the prevention and/or treatment of infectious diseases. The immunogenic compositions of the invention may also be used in combination with one or more antibiotics for the prevention and/or treatment of infectious diseases.
Properties of the immunogenic compositions of the invention
The immunogenic compositions of the invention have an unexpected effect on the immune response. As can be seen from the examples below, the immunogenic compositions of the invention show an unexpected technical effect of eliciting an immune response, which involves resetting, re-associating, directing, renewing and reprogramming the immune response in real time.
More specifically, the immunotherapeutic compositions of the invention are capable of inducing a reduction by establishing a new identity of the pathogen perceived by the innate and adaptive immune systems, and re-associating the operational functional capacity of the immune system against the power of the aggressor by altering relationships that allow the immune system to have a competitive advantage that does not occur spontaneously in the development of the disease. This re-contextualization determines the subsequent renewal and reprogramming of the established immune response, or the erroneous attack of the human or animal body in an abnormal way, so as to gradually restore the established immune response, or the erroneously established primary pro-inflammatory response, which is always an occasional response, which may be improved into a secondary, active anti-inflammatory, more effective and appropriate immune response.
This effect occurs through secondary stimulation, activation and combination of certain components of the immune system (e.g., sentinel cells, antigen presenting sentinel cells and memory lymphocytes). In particular, the compositions of the present invention properly recruit activated sentinel cells, activated dendritic cells and other activated APC cells through the action of memory cells, producing CD4T cells of a new degree and intensity, the secondary activation characteristic of which becomes a less effective criterion for the degree and intensity of the immune spectrum for the correct treatment of infection without causing immunological side effects (e.g., inflammation).
Thus, immunomodulatory antigenic compositions of the invention, when triggering specific active adaptive immune responses in greater or significant amounts, are expected to protect against bacterial, viral or parasitic infections in protection against neoplasms, cancers and tumors.
In addition, treatment with the immunogenic compositions of the invention can stimulate the regenerative capacity of the immune system, the natural physiological properties of which provide a subsequent effect for the elimination of infectious and other diseases: restoring cells and by restoring organ function weakened by trauma and damage that results in the loss of a portion of the body. This property was demonstrated in the clinical cases of irreversible sepsis reported in the examples. Patients have complex recovery and regeneration of traumatic wounds with significant tissue loss, CIVD-induced lung, kidney, liver, bone and limb organ destruction, and ischemic events with low blood flow and toxicity.
Thus, the immunogenic composition of the invention is capable of mobilizing the immune system and enhancing the regenerative capacity of the body by mobilizing stem cells or activating the genome, thereby regenerating cells and tissues, even organs and their functions, and organic systems such as the vascular system, nervous system, endocrine system, and the like.
As can be seen in the examples given below, the immunogenic compositions of the invention exhibit the unexpected technical effect of reconstituting, renewing and reprogramming the immune response in real time and thus have a significant cure rate, compared to the drugs and methods of the art.
In a first embodiment of the invention, specific concentrations of immunomodulators are used in the preparation of an immunotherapy pharmaceutical composition capable of inducing an innate immune response, which triggers a series of immune events, including activation of memory lymphocytes from agents vaccinated by manual intervention and concomitant activation by antigens present in the patient's own body, resulting in background reconstitution, renewal and reprogramming of an ongoing immune response against a particular established disease (or still in the establishment phase), thereby effectively producing an adaptive response specific for the disease, allowing protection against pathogens. Thus, administration of a composition comprising an agent of the invention, when the polarization established to date is insufficient, repolarizes or improves the polarization of the immune system in the presence of disease through the action of the pathogen or colonizer. The activity of the agents of the invention affects the shape, timing, accuracy and polarization of the immune response, preferably resulting in a specific innate and/or adaptive response that is more effective against disease, resulting in a better response of the organism itself.
The present invention provides methods for combating these types of xenogenic (infection and invasion) and autologous (tumor) challenges by using the described antigenic combinations. The invention also provides the following possibilities: adding conventional therapies to the agents of the invention helps eliminate etiological xeno-invaders and colonizing autologous cells by selecting the true therapeutic potential of antimicrobial, anticancer or other drugs for pathogens and other infectious agents. This may be done according to a shift principle favoring the biological balance of the patient in combination with the normal polarization of the immune response described herein.
When immune stimulation follows the regime of the immune response, at the end of the disease mechanism or invasion, the continuous activation of the immune system by the antigen or immunomodulator of the invention leads to the regeneration of tissues, organs and systems by mechanisms that are not yet fully understood, but are associated with the mechanisms of healing or complete recovery (restitution ad integrum) observed in various medical situations.
The compositions of the invention allow the recruitment of the maximum number of memory cells, new potent blasts of the individual, with a more pronounced effect than the increase in antibodies described in the prior art. The use of a plurality of antigenic agents with different abundant PAMPs and DAMPs to stimulate different types of attacks (the organisms are subjected to and to which the organisms already have immunological memory, by exposing the organisms to the environment or vaccination programs), allows a more extensive recruitment of memory and new cells, thus enabling a real-time background reconstitution of the immune response, thus potentially and fundamentally altering the type of immune response and affecting the disease or disease progression of the individual in a positive, in several cases so surprisingly, manner compared to the prior art. Furthermore, unlike the prior art, the present invention uses a greater amount of bacterial components (representative of intracellular and extracellular bacteria) in the composition in addition to the components of viruses, parasites, fungi and yeasts.
The present invention encompasses more areas of the body and tissue with sentinel helper APC cells and preferably seeks a secondary resetting innate system that is exposed to sites near the site of infection and other remote applications of the disease site (as manifested in the disease or illness) at specific locations of the body) to all places of the disease. The compositions of the invention, when administered according to the method of using the invention, in one or more, generally each, body part that is excreted in lymphoid regions or primary and/or secondary lymphoid organs or even lesions, are perceived by the PRRs (pathogen-associated pattern recognition receptors) of all sentinel cells of the body.
Thus, the present invention uses certain amounts, concentrations and specific locations of immunomodulators to reconstitute, reset and direct the immune system, activate and redirect mechanisms of tissue repair and regeneration, as occurs during healing and regeneration of a tissue, organ or system, resulting in "resilient integration" or reconstruction with scarring. This repair is usually triggered at the end of the course of the immune response after the infection has healed.
Use of the immunogenic compositions of the invention
In view of its properties, the immunogenic composition of the invention, which constitutes a further aspect of the invention, is used in the manufacture of a medicament for the prevention and/or treatment of infectious diseases.
These infectious diseases may be viruses, bacteria, fungi or parasites.
The diseases of viral origin prevented and/or treated by the immunogenic composition of the invention may be caused by (but are not limited to) the following viruses:
HIV, hepatitis virus, herpes virus, rhabdovirus, rubella virus, smallpox virus, poxvirus, measles virus, and paramyxovirus.
Diseases of bacterial origin prevented and/or treated by the immunogenic composition of the invention may be caused by (but are not limited to) the following bacteria: pneumococcus (Pneumococcus), staphylococci (Staphylococcus), Bacillus (Bacillus), Streptococcus (Streptococcus), Meningococcus (Meningococcus), Gonococcus (Gonococcus), Escherichia (Escherichia), Klebsiella (Klebsiella), Proteus (Proteus), Pseudomonas (Pseudomonas), Salmonella (Salmonella), Shigella (Shigella), Haemophilus (Haemophilus), Yersinia (Yersinia), Listeria (Listeria), Corynebacterium (Corynebacterium), Vibrio (Vibrio), clostridium (clostridium), Chlamydia (Chlamydia), Mycobacterium (Mycobacterium), Treponema (Treponema), and Helicobacter (Helicobacter).
Fungal diseases prevented and/or treated by the immunogenic compositions of the invention may be caused by (but are not limited to) the following fungi: candida, aspergillus, Cryptococcus neoformans and/or fungi causing superficial and deep mycoses. The diseases caused by parasites are caused by the following parasites: trypanosoma, schistosoma, Leishmania, Proteus, and Taenia.
In one embodiment of the invention, the composition of the invention is administered once in one area of the body or at different sites in order to redirect the immune system with as high an efficiency as possible.
The use of the immunogenic composition of the invention for modulating the immune system, including exposing part or all of the immune system to recognize antigens in the immune system, such as dendritic cells, macrophages and lymph nodes from different parts of the body, will depend on the target acted on by the disease to be combated and is preferably carried out by injection or using a gun (gun) or delivery system or controlled infusion or using pulsed cells of the antigens in vitro. The agent may be administered in the form of subcutaneous, intramuscular, intravenous, oral, inhalable aerosol, dermal (skin patch) administration in organs, viscera or specific tissues or in different body cavities, only at one site or at several tens of sites of the body, which may be administered in number from one to one hundred (100) times in one to fifty (50) sessions.
The antigenic compositions of the invention may also be combined with other drugs that can impair the reproduction, growth or any form of enhancement of the pathogens of the disease, thereby causing a shift in the balance that is favorable to the host, animal or human's biological immune defenses. Or still be present in a form that accompanies treatment.
Depending on the disease or illness to be combated in connection with inappropriate or ineffective immune activity, the antigenic composition of the invention may also be combined with other methods such as, but not limited to, antibiotics, chemotherapy, radiotherapy, therapy with antibodies and antisera, treatment with hormones or other physiological modulators (cytokines, chemokines, neurohormones, peptides), treatment with antiviral agents, use of herbs, vitamin supplementation, supplementation of pharmaceuticals with other cofactors or repair agents (prostheticalagents), methods of therapeutic or prophylactic vaccination (with or without cells, not limited to the type of vaccine vehicle), gene therapy, surgery or homeopathy.
Background reconstruction, reset, update, priming and reprogramming of immune responses.
As explained in the text of the present patent application, the re-framing and re-setting of the immune system is achieved by stimulating the immune system with antigens of different pathogens that are not related to the pathology to be treated, for humans or animals, preferably already having an immunological memory, which can completely change the internal perception original image of the pathogen of the intruder into a new actively induced secondary image.
These antigens may vary and many antigens, greater than 5 in number, have multiple PAMPs and DAMPs, induce vigorous activation in sentry cells and in APC cells, particularly in dendritic cells, allowing mobilization of these memory CD4 lymphocytes specific for these antigens at the site of administration.
These stimulants must be able to elicit a strong, powerful and effective secondary specific immune response against these antigens and a systemic mobilization of the immune system at the site of administration in regional lymph nodes, distant lymph nodes, so that they can elicit in parallel an effective response able to eliminate the specific pathology in progress.
The innate and adaptive immune responses intentionally elicited by the compositions of the present invention should encompass the entire range of, or even exceed, the body area affected by the condition to be treated, if it is possible to activate sentry and APC cells in amounts and intensities necessary to adequately cope with the attack caused by the pathogenic disease to be treated, and to activate and trigger the optimal specific adaptive response, continuous polarization with high efficiency and accuracy, to cure the condition to be treated.
Thus, the innate and adaptive responses induced by the present invention will geographically overlap with the condition to be treated and, by their strong and extensive activation, will correct the ineffective activation intentionally limited by the action of pathogens overcoming the body's defenses, by preventing competition, which properly mobilizes and generates an effective adaptive response according to their maximum genetic and biological potential. This ideal activation should also reverse the immunosuppressive, toleragenic and escape mechanisms established by pathogens, as it is known and demonstrated that a powerful unrelated immune response that completely covers the response to be corrected will efficiently correct these deficient situations by activated cells and cytokines of the immune system.
Effector cells and memory of the specific antigens of the invention, activated and produced at the site of antigen application, will pass through the blood stream through HEV into the already activated lymph nodes, thus draining the affected area of the disease and allowing it to induce activation of all existing dendritic cells there in a strong and intense manner. Thus, they will lead to activation of the entire lymph node, growing with increased irrigation, increasing its size, and making it a reactive lymph node capable of eliciting an immune response against weak antigens that are not themselves capable of eliciting an immune response. PAMPs alone can remodel lymph nodes supplying arterioles and induce lymph node hypertrophy, which is essential for both effective primary and secondary immune responses.
Effector/memory T lymphocytes are well known experimentally and clinically and have been experimentally demonstrated that this adjuvant effect will be opposed by the action of the target disease agent, which prevents lymph node activation that is required for the development of an immune response. Treating related diseases. For the purpose and effect of the present invention only, by its effective antigenic composition, the following may occur: the immune response sentinel cells and dendritic cells and macrophages are identical for unrelated and pathological antigens, but from this action will be strongly and correctly activated. Dendritic cells, which are strongly activated by various antigens, are slowly metabolized and ideally present all dominant and dominant epitopes of the pathogen through a known "helper" effect, thus mobilizing all possible and available T lymphocytes capable of specifically recognizing autologous or heterologous antigenic pathogens to treat and react to.
The area of inflammatory processes is identical to the lymphatic area. By their antigenic composition, the inflamed areas will block the inflammasome and exert an anti-inflammatory action that will correct the pathological inflammation responsible for the pathology of the disease and caused by its pathogens, by the anti-inflammatory action of the unrelated specific memory cells mobilized by the present invention. With regard to memory effects, it is important to note that this known role of memory T cells is primarily responsible for the fact that, after immunity has been established, secondary contact with any pathological factors is asymptomatic and does not cause disease.
The lymphatic regions are identical, but are now strongly activated and have the necessary alarm signal elicited by the invention to elicit any immune response, even against weak antigens, similar to what happens to dendritic cells (common to the invention) and to the autologous or heterologous pathogen to be defended. Lymphokines are the same as innate cells that control potent secondary responses, and T lymphocytes that are specific against the pathogen to be defended will "ride" the ideal microenvironment to maintain a potent immune response.
Dendritic cells activated by the present invention can capture antigens of the pathogen to be protected against in the site of the pathology and relevant lymphatic regions, and can be contacted with pathogen-specific TCD4 lymphocytes in a lymphatic system that can be modified and ideally activated. The action of the TCD4 mature dendritic cells, which are activated and matured by being specific for the pathogen, occurs in a microenvironment conducive to an immune response with the full genetic and biological potential of the host organism's immune system.
Such dendritic cells at the site of disease and lymph nodes can be correctly assessed for the severity, extent, intensity and type of invasion, thereby activating, inducing, co-operating, polarizing, leading and maintaining a new effective adaptive immune response, whose effector circuit, in cooperation with the strong correctly activated innate immune cells and effector molecules, can be able to eliminate the pathogen to be defended against. The answer is thus reprogrammed and brought back (as indicated by the background), reversing the biological balance that was previously under control of autologous or xenogenic disease factors to favor the host.
This effect can occur with or without the aid of biological balance shifters, such as antibiotics and anticancer drugs, capable of blocking, attenuating or neutralizing the effects and potential of pathogens, thereby allowing the immune system the opportunity to cure the pathology targeted for treatment. Once triggered by any pathogen, the immune system will only stop reacting when the pathogen is eliminated or the organism dies, so the present invention will help to avoid the latter option, or it may ameliorate the condition of the patient if it is an incurable chronic disease.
Thus, intentionally and strategically overlapping the effect of the composition of the invention over the entire area under the effect of the agent to be combated will background reconstitute the immune system by activating PAMPs and DAMPs in sentry cells and common APCs and by unrelated specific secondary adaptive immune responses. This deliberately induced immune response will efficiently activate the entire lymphatic region and the organ regions affected by the pathogen. In the background restructuring region and in the bulge (bull), in the context of the larger immune response, the stronger, more intense and more extensive secondary anti-inflammatory properties of the target immune response, as described, will be reprogrammed and efficiently renewed within a range of greater opportunities for the host, with existing opportunities to reverse the biological equilibrium toward its favor.
Principles of treatment protocols
The treatment regimen of the present invention designed for cases of bacterial infection and sepsis must:
the most strategic lymphatic regions for body or infection. In the case described herein, more than 10 lymphatic regions have been selected. It must be used within tumors and in infected and damaged areas.
The immunotherapy preparation must contain at least 5 antigens so that it contains PAMPs and DAMPs in order to be able to background reconstitute the immune system.
The application areas must overlap, cover and exceed the entire extension of the area occupied by the tumor and the infection.
Antigenic stimulation must be repeated every 4 or 5 days to avoid suppressor cell production or suppression of the obtained repolarization that could halt the new desired immune response.
The treatment must be maintained in this way until the end of the infection or the healing of the wound, organ or system.
In fact, 1 to 3ml of this immunotherapy must be applied to 10 or more lymphatic zones. The present invention should be applied to both the inside of a lesion caused by infection and the site of the lesion.
In summary, immunotherapy is distributed "systemically" around and within several (at least ten) lymphatic lesions, the volume of which is capable of disrupting and destroying the lesions from microscopic and macroscopic environments, or covering the area severely affected by infection and inflammation, and restoring a microenvironment favorable to the immune response of the organism. It will be applied every 4 to 5 days.
In sepsis, severe sepsis and septic shock, the use of low doses of exogenous interleukin-2 should be avoided. When an amplification of the immune loop is required, it should be carefully assessed that low doses of exogenous interleukin-2 are used without interruption in severe infections.
Examples
In order to better understand the invention and to clearly illustrate the technological advances made, the results of various tests carried out on the invention are shown below as examples.
These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Example 1: immunogenic compositions
In order to achieve the reconstitution, renewal and reprogramming of an immune response in real time according to the innovative concepts described in the present invention, a person skilled in the art can design different and different product compositions, combinations or formulations, which fall within the scope of the present invention.
As mentioned above, for such compositions, in order to meet the technical requirements of beneficial or undisclosed results for the treatment of many diseases and disorders, they must have a high diversity of antigens from pathogens in order to obtain the maximum synergistic effect in binding PAMPs and DAMPs to their receptors and to allow a high activation of innate immunity in sentry cells (with or without ATC function) allowing the reconstitution, renewal and reprogramming of immune responses in real time.
Such compositions should preferably employ antigenic agents, and due to prior exposure, memory clones in the immune system of most humans are capable of inducing extensive anti-inflammatory effects while reorganizing. For this reason, the antigenic agent should preferably be selected:
corresponds to the most common infection that an individual suffers from childhood to maturity (when the animal or human acquires its "immune spectrum").
For immunization programs, such as vaccination programs for children against endemic and/or epidemic diseases.
Organisms from potentially pathogenic microflora, in particular the gastrointestinal tract, in which memory lymphocytes play an active dynamic barrier, ensuring the survival of the individual.
Ideally, the concentration of each antigen drug should be 0.001 to 500 micrograms/ml.
Based on these concepts, several formulations have been developed for use in human vaccination programs or allergy tests and immune evaluation tests using antigenic agents in their existing, safe and approved forms.
We therefore present several examples of compositions which fall within the scope of the present invention, but are not intended to be limiting thereof, as the present invention and its concept allows the design of immunogenic compositions comprising a combination of a large number of antigenic agents.
Composition 1a (DECA composition):
composition 1b (VITER composition)
Composition 2:
composition 3:
composition 4:
composition 5:
composition 6:
composition 7:
composition 8:
composition 9:
composition 10:
composition 11:
composition 12:
composition 13:
composition 14:
composition 15:
composition 16:
composition 17:
composition 18:
composition 19:
composition 20:
composition 21:
composition 22
Composition 23:
composition 24:
composition 25:
composition 26:
composition 27:
composition 28:
composition 29:
composition 30:
composition 31:
composition 32:
composition 33:
composition 34:
composition 35:
composition 36:
when there is a parasitic disease associated or to be combated, the preparation will preferentially contain the antigenicity of the parasitic source. In this case, according to the concept described in the present invention, the preparation should contain antigenic agents derived from the most prevalent parasites, where the individual has more memory cells, according to the geographical distribution and the local and regional human development (developed or non-developed countries). These parameters determine the occurrence of these parasites and the presence of corresponding memory cells in the immune system of a given area population.
Composition 37: combination of composition 2 with:
components | Concentration of |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Composition 38: combination of composition 3 with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Composition 39: combination of composition 4 with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 40: combination of composition 5 with:
components | Concentration of |
Inactivated human roundworm lysate | 400μg/mL |
Composition 41: composition 6 in combination with:
components | Concentration of |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 42: combination of composition 7 with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 43: combination of composition 8 with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 44: composition 9 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 45: combination of composition 10 with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 46: combination of composition 11 with:
components | Concentration of |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 47: composition 12 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Cryptosporidium lysate | 400μg/mL |
Composition 48: composition 13 in combination with:
components | Concentration of |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Composition 49: combination of composition 14 with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Composition 50: composition 15 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 51: combination of composition 16 with:
components | Concentration of |
Inactivated Trichomonas vaginalis lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 52: composition 17 in combination with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 53: combination of composition 18 with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Composition 54: combination of composition 19 with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Composition 55: combination of composition 20 with:
composition 56: combination of composition 21 with:
components | Concentration of |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Composition 57: combination of composition 22 with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Cryptosporidium lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 58: combination of composition 23 with:
components | Concentration of |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 59: composition 24 in combination with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 60: composition 25 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 61: combination of composition 26 with:
components | Concentration of |
Inactivated Trichomonas vaginalis lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Composition 62: composition 27 in combination with:
composition 63: composition 28 in combination with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 64: composition 29 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 65: composition 30 in combination with:
components | Concentration of |
Inactivated giardia lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Composition 66: combination of composition 31 with:
components | Concentration of |
Inactivated Toxoplasma gondii lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Composition 67: composition 32 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated Cryptosporidium lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Composition 68: combination of composition 33 with:
composition 69: combination of composition 34 with:
components | Concentration of |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated Trichomonas vaginalis lysate | 400μg/mL |
Composition 70: composition 35 in combination with:
components | Concentration of |
Inactivated strongyloides faecalis lysate | 400μg/mL |
Inactivated human enterobiasis lysate | 400μg/mL |
Inactivated Enzymospecific Entamoeba lysate | 400μg/mL |
Inactivated Cryptosporidium lysate | 400μg/mL |
Composition 71: composition 36 in combination with:
components | Concentration of |
Inactivated Trichomonas vaginalis lysate | 400μg/mL |
Inactivated human roundworm lysate | 400μg/mL |
Inactivated giardia lysate | 400μg/mL |
Example 2: treating septicemia
Patient data
Patient J-P, 58 years old, male.
Major diagnosis
Sepsis.
Secondary diagnosis
Multiple wounds having:
complicated infected wounds, tissue loss of about 40 cm.
Tissue necrosis with widespread infection, suggesting amputation of the left lower limb.
Infected grade IIIB open fractures were accompanied by left femoral osteomyelitis and were exposed laterally.
Open wounds on the left arm, the posterior side of the left foot, and the right lateral malleolus area, infected contusion wounds, all were not sutured.
Identification and summary of clinical history
The patient was admitted to the orthodox intensive care unit of octaian Constantine hospital dass clinics of terebrapolis at 12 days 1/2011, and a landslide victim had a left femoral grade IIIb open fracture and exposed lateral and medial incisions. Contusion extending 40 cm in depth was associated with exposure of the sides. Laceration and contusion occur in the left arm, the back of the left foot and the right lateral malleolus area. Sepsis developed within 24 hours, identified by pseudomonas aeruginosa microorganisms.
Routine recommendations and implemented treatments
The femur was fixed outside the emergency room, given clindamycin, vancomycin, and cefepime, and surgical debridement was performed daily.
Results of performing routine treatments
Initially, the condition of sepsis is ameliorated, followed by a progression to infection of the left lower limb with extensive areas of muscle necrosis and a high risk of amputation. 15 days after admission, sepsis became worse, with a high fever attack at 39 ℃, severe anemia (receiving blood transfusion) and exchange of antibacterial drugs for Tazocim. The patient is transferred to saint paul under medical supervision via an aerial intensive care unit.
Termination of conventional treatment showed recurrence of sepsis, increased necrosis of the left leg, suggesting amputation.
Suggesting DECA treatment in connection with conventional surgical treatment
administration of 1.8cc of the DECA composition along 10 major lymphatic vessel regions, divided into 2 compositions, each composition of 0.9 cc.
The interval between the two applications was 3-4 cm, in order to read the progress of the treatment every 4 ± 1 day. These applications were performed with surgical debridement (on average 1 to 2 times per week).
In two applications of 0.9cc each, 36 additional perilesional components of each DECA were administered, avoiding the following open sutures which could not be sutured: the left groin area, the left thigh lateral side, the left thigh anterior side and the left thigh medial side, the instep area, and the left lateral ankle of the right leg.
The use of low doses of recombinant human interleukin 2, with receptor saturation levels of 1 to 2 million units per square meter of patient body surface, in additional DECA dosing zones. The patient is injected subcutaneously into the left thigh or groin area 300 ten thousand units per day.
In the exposed areas, 15 DECA compositions (1.8 cc each) were applied to penetrate the bare virgin areas.
This extensive immunotherapy is always applied during the surgical period of cleansing and surgical debridement under general anesthesia.
Thus, the first round of immunotherapy started on day 29 of 2011 and ended on day 19 of 2011 on day 3, a total of 9 DECA's were performed once to twice a week after following the cleaning and debridement schedule between procedures (risk of infection due to severity of pain and extensive exposure of internal tissues in the original area).
DECA treatment outcomes in connection with surgical debridement and antibiotic treatment
The patient was initially assessed for injury in the operating room on day 1/29 of 2011 and the results showed that all wounds were bleeding with many blood clots, large areas of necrosis and pus. Following surgical cleaning, the tissue continued to perform poorly, appeared white in appearance, and no healthy granulation tissue appeared (fig. 1-a 1, A3, and a 4). As mentioned above, DECA immunotherapy has been applied in these areas. Interestingly, in this case, the culture of internal secretions and tissue fragments was performed.
After 24 hours, surgical treatment associated with DECA immunotherapy was first evaluated and the results indicated: red lesions, healthy granulation tissue appearance, few necrotic areas, less secretion and no odor, no active bleeding. Lesions were cleared and DECA immunotherapy was performed as described above. In this case, the antibiotic therapy was changed to Tazocim Meronem, daptomycin and rifamycin results to be cultured.
The culture results from the injured area, peripheral blood and central catheter on day 1/2 of 2011 showed:
the multidrug-resistant Pseudomonas aeruginosa, only the multidrug-resistant Acinetobacter baumannii susceptible to polymyxin B and multidrug-resistant Proteus mirabiles, was isolated in the left thigh wound.
Isolation of multidrug-resistant acinetobacter baumannii sensitive only to polymyxin B in peripheral blood and central catheter.
And (4) conclusion: these results indicate that poor prognosis of left leg injury leads to the onset of new sepsis by acinetobacter baumannii and, due to its multidrug resistance and sensitivity to polymyxin B only, does not respond to intravenous treatment with tazobactam. On the other hand, it strongly supports the beneficial effect of the DECA composition in the local and systemic protection of such infections in combination surgical treatment, since systemic infections and injuries are improved before the administration of polymyxin B neutralizes the pathogen.
On the day, Meronem was replaced with 20,000IU/kg of polymyxin B twice daily without any other drug replacement.
On day 3/2 of 2011, antibiotic therapy, debridement and DECA immunotherapy were found to combine to result in remission of sepsis, thereby transferring the patient from the ICU to the ward (fig. 1-B1, B2 and B3).
On day 6/2 of 2011, the patient presented with acute oliguric renal failure in view of the toxicity of taking polymyxin B and other antimicrobial drugs. As a result, the use of these antibiotics was suspended during the period of 2011 from 6 days 2 to 2011 from 15 days 2 (12 days), and limezolida (zyvox) was introduced to prevent staphylococcal contamination in hospitals. On day 2, 15 of 2011, complete remission of renal failure was confirmed. During this 12 day period, the patient's infection and injury generally progressed well with only the combined treatment of debridement, antibiotic prophylaxis and DECA immunotherapy, during which time the patient could pull out the external fixator, perform surgical cleanup, and introduce an internal rod for fixing the fracture in a surgical procedure performed on day 2/17 of 2011. Thus, during this period, together with plastic surgery, the skin area without skin is significantly reduced, without extensive tissue regeneration, and without new infections.
The patient was discharged 3/15 days 2011 and completely cured all complex injuries and wounds, including infection with osteomyelitis. The patient was discharged without antibiotic treatment.
Summary of the present disclosure
The severe and widespread infection and the presence of complex wounds infects multi-drug resistant acinetobacter baumannii, which is sensitive only to polymyxin B, and sepsis can be controlled without special antibiotic treatment, and the cure of all exposed lesions and osteomyelitis strongly suggests a decisive role for the healing of clinical conditions in a relatively short time with debridement and antibiotic-related DECA immunotherapy.
Table 1 relevant results of DECA immunotherapy, antibiotics and surgical debridement for sepsis and severe infections of complex wounds.
Example 3: treatment of sepsis associated with urinary infections and advanced gastric cancer with oropharyngeal cancer
Patient information
Patient CMS-female, 38 years old.
Diagnosis of
In 2011, 10, 3 days, late gastric cancer is complicated with aspiration pneumonia, chemical pneumonia and infectious pneumonia, and urinary tract and oropharynx infections are complicated with septicemia. Both central catheter and tracheal broth cultures were positive for pseudomonas aeruginosa (serratia marcescens isolated only in tracheal aspirates). Multiple drug resistant klebsiella pneumoniae sensitive only to IMIPENEM and its derivatives was isolated by urine culture. In ICU, sepsis is characterized by hemodynamic changes and breakdown, initially requiring the use of vasoactive drugs and respiratory support to control the onset. The patient also developed platelet obstruction with severe anemia and with acute anemia (hemoglobin 8.6g/dL), hypokalemia, hyponatremia and lymphopenia (lymphocyte count of 3,000/microliter).
Previous conventional treatment
Antibiotic therapy, vasoactive drugs, respiratory support and parenteral nutrition.
VITER treatment
With the patient's informed consent, one immunotherapy was performed 10/4/2011. VITER immunotherapy is as follows:
each of the VITER preparations (example 1) was used at 0.2 mL. Attenuated yellow fever virus strain 17D204, 20 μ g/mL, was used near the main 10 lymphatic vessel regions.
Low doses of recombinant human interleukin 2 are used at receptor saturation levels, at concentrations of 1 to 2 million units per meter of body surface.
Results of VITER immunotherapy
7/10/2011, anemia and thrombocytopenia were reversed, platelet counts were 178,000/microliter, and platelet aggregation function was compatible with normal parameters. Normalization of serum electrolytes was also noted. As lymphocyte counts increased from 3,000/microliter at 3 days 10/month 2011 to 9,400/microliter at 7 days 10/month 2011, immunostimulation caused restoration of immune competence and activation of effector T-loops. The C-reactive protein concentration decreased to 61mg/l, indicating that infection was controlled. It is worth mentioning that patients are still receiving other immunotherapy in "home care" nursing homes. Aspiration pneumonia was confirmed by chest X-ray examination on day 1/11 in 2011, and then a dramatic recovery was obtained after 3 days of immunotherapy with combination antibacterial therapy (fig. 2).
Case conclusion
Transfer from hospital to home care was made in 2011, 10, and 9 days. Evaluation data and clinical course of the patients indicate that innovative immunotherapy allows patients to achieve striking recovery from the severe sepsis they are in. The continuity of immunostimulatory therapy also contributes to improved quality of life and dramatic improvement in patients over their expected life. According to the prior art, this widespread and terminal cancer condition results in death within about 1 month, whereas the immune stimulation of the present invention allows an unexpected survival of one and a half years, with the accompanying of the parent.
Example 4: treatment of infection (multidrug resistant bacteria for SARS in septic shock)
Patient information
Patient AMB-female, 39 years old.
Preliminary diagnosis
Severe septicemia and septic shock
Secondary diagnosis
Indicated as complications:
severe Acute Respiratory Syndrome (SARS);
-shock;
-acute renal failure;
-disseminated intravascular coagulation;
-signs of liver failure;
identification and summary of clinical history
Day 19 of 2007 was diagnosed with community pneumonia, non-cough and high fever. After 10 hours of admission, the patient worsens, needs to be referred to an Intensive Care Unit (ICU), and has respiratory tract infection and septic shock, which are characterized in that: hypertension, SARS; kidney and liver failure; disseminated intravascular coagulation; serum lactate increase, hemodynamics and electrolyte depletion.
Previous conventional treatment
In 2007, after 20 days 4, ceftriaxone sodium and levofloxacin were used for treatment. However, when it becomes necessary following clinical complications and ICU admission: i) initiating respiratory and hemodynamic support; ii) replacing the antibacterial agent with meropenem and vancomycin; iii) infusion of plasma 08U and IV active protein C can reverse disseminated intravascular coagulation and make opsonization possible. Despite all efforts, patients have not achieved any clinical and laboratory improvement.
IRS suggesting DECA treatment in combination with conventional therapy
After informed consent, 9 courses of immunotherapy were performed starting from day 21, 4 months, 2011. The method of performing DECA immunotherapy is as follows:
each of the 10 antigenic components was used at 0.2mL (1. Koch tuberculin (inactivated M.bovis lysate 0.0036ng/mL), 2.PPD (0.0036. mu.g/mL), 3. inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis, aliquot, 6.31. mu.g/mL), 4. inactivated Streptococcus lysate (Streptococcus pyogenes, Streptococcus pneumoniae and enterococcus faecalis, aliquot, 6.31. mu.g/mL), 5. inactivated and purified streptokinase derived from beta-hemolytic Streptococcus lysate, 0.404. mu.g/mL, 6. inactivated and purified streptococcal enzyme derived from beta-hemolytic Streptococcus lysate, 0.101. mu.g/mL, 7. Candida (antigenic extract of Candida albicans, 6.31. mu.g/mL), 8. trichophyton (antigenic extract of Trichophyton 6.31. mu.g/mL), 9. inactivated Escherichia coli lysate (EPEC 6.31. mu.g/mL) (ii) a 10. Inactivated Salmonella lysate (Salmonella bongofer, Salmonella enterica, and Salmonella subterranean, aliquot, 6.31. mu.g/mL)).
IRS-DECA immunotherapy combined with conventional treatment outcomes
26/5/2007, serum electrolyte and lactate levels reached normal levels, platelets reversed, and platelet counts were 167,000/mm3And the platelet aggregation function returns to normal. On 27 days 4 month 2007 SARS was still very severe but began to improve. 29 th month 5 2007, saturation and pO of arterial blood gas analysis2Reversal, indicating hemodynamic recovery. Immunostimulation results in restoration of immune competence and activation of effector T-loops with standardized complement components at 28.4.2007, lymphocyte counts from 21.100/mm at 20.4.20073(4-22-day deterioration to 43.700/mm in 20073) Reduced to 11.000/mm in 30 days 4 months in 20073CD3, CD4 and CD8 fractions exhibited appropriate levels. After 29 days 4-2007, respiratory system conditions were greatly improved and respiratory support was removed. Patients were discharged from ICU on 6 days 5-2007 and severe sepsis had completely recovered. Community pneumonia was diagnosed at 19 th of 2007, confirmed by chest X-ray examination at 24 th of 2007 (fig. 3-a1), exacerbation to SARS associated with sepsis was confirmed by CT scan at 27 th of 2007 at 4 th of 2007 (fig. 3-B1 to B6), and after 15 days of immunotherapy combined with antibacterial treatment (6 courses), there was an astonishing recovery by laboratory and X-ray examination at 6 th of 2007 at 5 th of 2007 (fig. 3-C1).
Case conclusion
Discharged from the hospital on 6/5/2007. Patient evaluation data and clinical course indicate that innovative immunotherapy can surprisingly recover from severe sepsis and septic shock conditions in which patients are exposed. The continuity of immunostimulatory therapy also helps to completely eradicate severe infections and significantly improve life expectancy. According to the prior art, in septic shock associated with renal and hepatic failure conditions, multi-resistant bacteria such as SARS cause death within hours, while unexpected survival without sequelae is possible by the immunostimulation of the present invention.
In short, the clinical cases presented above demonstrate that by using the IRS compositions of the invention, highly complex diseases and conditions with very poor prognosis are more correctly solved in an advantageous and more efficient way.
Reference to the literature
For a better understanding of the above concepts and definitions relating to the present invention, the following references are incorporated into this patent application:
1.Pulendran B.The varieties of immunological experience:of pathogens,stress,and dendritic cells.Annual review of immunology.2015;33:563-606.
2.Steinman RM.Decisions about dendritic cells:past,present,andfuture.Annual review of immunology.2012;30:1-22.
3.Steinman RM,Banchereau J.Taking dendritic cells intomedicine.Nature.2007;449(7161):419-26.
Martin-Fontecha A, Baumjohann D, Guarda G, Reboldi A, Hons M, Lanzavecchia A, etc. CD40L + CD4+ memory T cells fine in a CD62P-dependent frequency in reactive templates and reactive cells for T cells printing, the Journal of experimental media.2008; 205(11):2561-74.
5.Soderberg KA,Payne GW,Sato A,Medzhitov R,Segal SS,Iwasaki A.Innatecontrol of adaptive immunity via remodeling of lymph node feedarteriole.Proceedings of the National Academy of Sciences of the UnitedStates of America.2005;102(45):16315-20.
Memory CD8+ T cells media activity CCL3 activity of TNF/ROI + Phagocytes, the Journal of experimental media 2007, etc.; 204(9):2075-87.
7.Jeffrey K.Rechallenging immunological memory.Nature medicine.2007;13(10):1142.
8.Weisel FJ,Zuccarino-Catania GV,Chikina M,Shlomchik MJ.ATemporalSwitch in the Germinal Center Determines Differential Output of Memory B andPlasma Cells.Immunity.2016;44(1):116-30.
9.De Silva NS,KleinU.Dynamics of B cells in germinal centres.Nat RevImmunol.2015;15(3):137-48.
10.Sallusto F,Monticelli S.The many faces of CD4 T cells:roles inimmunity and disease.Seminars in immunology.2013;25(4):249-51.
11.Sallusto F,Lanzavecchia A.Heterogeneity of CD4+memory T cells:functional modules for tailored immunity.European journal of immunology.2009;39(8):2076-82.
Becattini S, Latore D, Mel F, Fogliorini M, De Gregorio C, Cassotta A, etc. T cell immunity. functional homology of human memory CD4(+) T cell clones printed by Pathologens or vaccins. science.2015; 347(6220):400-6.
13.Zhu J,Paul WE.CD4 T cells:fates,functions,and faults.Blood.2008;112(5):1557-69.
14.Sallusto F,Zielinski CE,Lanzavecchia A.Human Th17 subsets.Europeanjournal of immunology.2012;42(9):2215-20.
15.Duhen T,Duhen R,Lanzavecchia A,Sallusto F,Campbell DJ.Functionallydistinct subsets of human FOXP3+Treg cells that phenotypically mirroreffector Th cells.Blood.2012;119(19):4430-40.
16.Crotty S.Follicular helper CD4 T cells(TFH).Annual review ofimmunology.2011;29:621-63.
17.Zielinski CE,Corti D,Mele F,Pinto D,Lanzavecchia A,SallustoF.Dissecting the human immunologic memory for pathogens.Immunologicalreviews.2011;240(1):40-51.
The Public reproduction of xenograms Enables Discovery and random amplified Phase II-like Trials in Rice cell.2016; 29(4):574-86.
19.In this issue.Nature Reviews Immunology.2016;16(2):69-.
20.Cerwenka A,Lanier LL.Natural killer cell memory in infection,inflammation and cancer.Nat Rev Immunol.2016;16(2):112-23.
21.Leavy O.Immune memory:T-box tuning for TRM cell fate.Nat RevImmunol.2016;16(2):71.
Mackay LK, Wynne-Jones E, Freestone D, Pellicci DG, Mielke LA, NewmanDM et al T-box transformation Factors Combine with the Cytokines TGF-beta and IL-15to Immunity.2015; 43(6) 1101-11 LID-10.016/j.immun.2015.11.008 [ doi ] LID-S1074-7613(15)00460-4[ pii ].
23.Bird L.Immune memory:ILC2s drive allergen recall.Nat RevImmunol.2016;16(2):72-3.
Group2 input ghost cells license polymeric cells to porous media TH2 cell responses Nat Immunol.2016; 17(1):57-64.
25.Leavy O.Immune memory:Sequential evolution of B cell memory.NatRev Immunol.2016;16(2):72-3.
26.Kugelberg E.Immune memory:Lingering human T cells.Nat RevImmunol.2016;16(2):73.
Oliveira G, Ruggiero E, Stanghellini MT, Cieri N, D' Agostino M, Fronzar et al, Tracking genetic engineered lympocytics long-term improvements the dynamics of T.Sci Transl Med.2015; 7(317) 317ra198 LID-10.1126/scitranslim. aac8265[ doi ].
28.Mueller SN,Mackay LK.Tissue-resident memory T cells:localspecialists in immune defence.Nat Rev Immunol.2016;16(2):79-89.
29.Rosenblum MD,Way SS,Abbas AK.Regulatory T cell memory.Nat RevImmunol.2016;16(2):90-101.
30.Farber DL,Netea MG,Radbruch A,Rajewsky K,ZinkernagelRM.Immunological memory:lessons from the past and a look to the future.NatRev Immunol.2016;16(2):124-8.
31.Laidlaw BJ,Craft JE,Kaech SM.The multifaceted role of CD4(+)Tcells in CD8(+)T cell memory.Nat Rev Immunol.2016;16(2):102-11LID-10.1038/nri.2015.10[doi].
32.Tubo NJ,Fife BT,Pagan AJ,Kotov DI,Goldberg MF,Jenkins MK.Mostmicrobe-specific naive CD4(+)T cells produce memory cells duringinfection.Science.2016;351(6272):511-4.
Flierl MA, Rittirsch D, Gao H, Hoesel LM, Nadeau BA, Day DE et al, Adverse functions of IL-17A in Experimental section, FASEB j ournal of the scientific publication of the Federation of American society for Experimental biology.2008; 22(7):2198-205.
34.Xiao H,Siddiqui J,Remick DG.Mechanisms of mortality in early andlate sepsis.Infection and immunity.2006;74(9):5227-35.
35.Buras JA,Holzmann B,Sitkovsky M.Animal models of sepsis:settingthe stage.Nature reviews Drug discovery.2005;4(10):854-65.
36.DiPaolo RJ,Shevach EM.CD4+T-cell development in a mouse expressinga transgenic TCR derived from a Treg.Eur J Immunol.2009;39(1):234-40.
Weber SU, Schewe JC, Lehmann LE, Muller S, Book M, Klaschik S, etc. indication of Bim and Bid gene expression reduced associated adaptive approach in turbine stage. crit Care.2008; 12(5) R128.
Bim siRNA discovery cell approach and improvis Survival involvement. Shock.2008; 30(2):127-34.
Martignoni A, Tschop J, Goetzman HS, Choi LG, Reid MD, Johannigman JA et al, CD4-expressing cell array indicators of the input animal system during session.2008; 29(5):591-7.
40.Schmoeckel K,Traffehn S,Eger C,Potschke C,Broker BM.Fullactivation of CD4+T cells early during sepsis requires specificantigen.Shock.2015;43(2):192-200.
41.Latifi SQ,O'Riordan MA,Levine AD.Interleukin-10controls the onsetof irreversible septic shock.Infection and immunity.2002;70(8):4441-6.
Querec T, Bennouna S Fau-Alkan S, Alkan S Fau-Laouar Y, Laouar Y Fau-Gorden K, Gorden K Fau-Flavell R, Flavell R Fau-Akira S, etc. Yellow river vaccineYF-17D actives multiple driver cell subst via TLR2.J Exp Med 2006; 203(2):413-24.
Pulendran B, Miller J, Querec TD, Akondy R, Moseley N, Laur O, etc. Case of yellow river vaccine, associated viral diagnostic with project diagnostic, robust adaptive immune responses, and polymorphins in CCR5 and RANTES genes, the Journal of infectious diseases, 2008; 198(4):500-7.
44.Nakaya HI,Pulendran B.Vaccinology in the era of high-throughputbiology.Philosophical transactions of the Royal Society of London Series B,Biological sciences.2015;370(1671).
45.Hagan T,Nakaya HI,Subramaniam S,Pulendran B.Systems vaccinology:Enabling rational vaccine design with systems biologicalapproaches.Vaccine.2015.
46.Li S,Nakaya HI,Kazmin DA,Oh JZ,Pulendran B.Systems biologicalapproaches to measure and understand vaccine immunity in humans.Seminars inimmunology.2013;25(3):209-18.
47.Pulendran B,Ahmed R.Immunological mechanisms of vaccination.Natureimmunology.2011;12(6):509-17.
48.Buonaguro L,Pulendran B.Immunogenomics and systems biology ofvaccines.Immunological reviews.2011;239(1):197-208.
49.Pulendran B,Li S,Nakaya HI.Systems vaccinology.Immunity.2010;33(4):516-29.
50.Ahmed R,Pulendran B.Learning vaccinology from viral infections.TheJournal of experimental medicine.2011;208(12):2347-9.
51.Edward F.McCarthy MD.THE TOXINS OF WILLIAM B.COLEY AND THETREATMENT OF BONE AND SOFT-TISSUE SARCOMAS.The Iowa Orthopaedic Journal.2006;26.
52.Waldner H.Activation of antigen-presenting cells by microbialproducts breaks self tolerance and induces autoimmune disease.Journal ofClinical Investigation.2004;113(7):990-7.
53.Maryanski JL,Boon T.Immunogenic variants obtained by mutagenesisof mouse mastocytoma P815.IV.Analysis of variant-specific antigens byselection of antigen-loss variants with cytolytic T cell clones.Europeanjournal of immunology.1982;12(5):406-12.
54.Boon T,Maryanski J.Tumour cell variants with increasedimmunogenicity obtained by mutagen treatment.Cancer Surv.1985;4(1):135-48.
55.Koguchi Y,Thauland TJ,Slifka MK,Parker DC.Preformed CD40 ligandexists in secretory lysosomes in effector and memory CD4+T cells and isquickly expressed on the cell surface in an antigen-specificmanner.Blood.2007;110(7):2520-7.
56.Narni-Mancinelli E, Soudja SM, Crozat K, Dalod M, Gounon P, Geissmann F, etc. Inflummatory monocytes and neutrophiles are sensitive to kill during monomers in vivo. PLoS Pathogens.2011; and (7), (12) e1002457.
57.Narni-Mancinelli E,Vivier E.Delivering three punches to knockoutintracellular bacteria.Cell.2014;157(6):1251-2.
58.Bajenoff M,Narni-Mancinelli E,Brau F,Lauvau G.Visualizing earlysplenic memory CD8+T cells reactivation against intracellular bacteria in themouse.PloS one.2010;5(7):e11524.
59.Soudja SM,Ruiz AL,Marie JC,Lauvau G.Inflammatory monocytesactivate memory CD8(+)T and innate NK lymphocytes independent of cognateantigen during microbial pathogen invasion.Immunity.2012;37(3):549-62.
60.Kohlhapp FJ,Kaufman HL.Molecular Pathways:Mechanism of Action forTalimogene Laherparepvec,a New Oncolytic Virus Immunotherapy.Clinical cancerresearch:an official journal of the American Association for CancerResearch.2016;22(5):1048-54.
61.Topalian SL, Wolchok JD, Chan TA, Mellman I, Palucka K, Banchereau J et al. Cell.2015; 161(2):185-6.
62.Kaufman HL.Vaccines for melanoma and renal cell carcinoma.Seminarsin oncology.2012;39(3):263-75.
63.Glimcher LH,Lindvall O,Aguirre V,Topalian SL,Musunuru K,FauciAS.Translating research into therapies.Cell.2012;148(6):1077-8.
Nakaya HI, Wrammert J, Lee EK, Raciopi L, Marie-Kunze S, Haining WN et al Systems biology of vaccination for search infla in humans. Natureimemunology.2011; 12(8):786-95.
65.Sallusto F,Lanzavecchia A,Araki K,Ahmed R.From vaccines to memoryand back.Immunity.2010;33(4):451-63.
66.Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D et al, Systemmicrobiology apple prediction of the yellow river vaccine in humanans Nature immunology 2009; 10(1):116-25.
67.Amanna IJ,Carlson NE,Slifka MK.Duration of humoral immunity tocommon viral and vaccine antigens.The New England journal of medicine.2007;357(19):1903-15.
68.Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, FlavelR, et al. yellowowfe vaccine YF-17D activities multiple dendritic cell subsets via TLR2,7,8, and 9to a substrate polymeric immunity. the Journal of experimental media.2006; 203(2):413-24.
69.Pulendran B,Ahmed R.Translating innate immunity into immunologicalmemory:implications for vaccine development.Cell.2006;124(4):849-63.
70.Amanna IJ,Slifka MK,Crotty S.Immunity and immunological memoryfollowing smallpox vaccination.Immunological reviews.2006;211:320-37.
71.Arlen PM,Kaufman HL,DiPaola RS.Pox viral vaccineapproaches.Seminars in oncology.2005;32(6):549-55.
Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, et al Duration of antiviral after Small vaccine. Naturemcine.2003; 9(9):1131-7.
73.Crotty S,Felgner P,Davies H,Glidewell J,Villarreal L,AhmedR.Cutting edge:long-term B cell memory in humans after smallpoxvaccination.Journal of immunology.2003;171(10):4969-73.
74.Cono J,Casey CG,Bell DM,Centers for Disease C,Prevention.Smallpoxvaccination and adverse reactions.Guidance for clinicians.MMWR RecommRep.2003;52(RR-4):1-28.
Clinical responses to undiluted and partitioned smallpox vaccine, the New England and journal of media, 2002; 346(17):1265-74.
76.Ahmed R,Gray D.Immunological memory and protective immunity:understanding their relation.Science.1996;272(5258):54-60.
77.Koplan JP,Marton KI.Smallpox vaccination revisited.Someobservations on the biology of vaccinia.The American journal of tropicalmedicine and hygiene.1975;24(4):656-63.
78.Theiler M,Smith HH.The Use of Yellow Fever Virus Modified by inVitro Cultivation for Human Immunization.The Journal of experimentalmedicine.1937;65(6):787-800。
Claims (7)
1. A pharmaceutical product comprising one or more antibiotics and one or more IRS immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more synthetic or natural antigenic agents, or parts and combinations thereof, and one or more physiologically acceptable carriers, excipients, diluents, or solvents; the synthetic or natural antigenic agent comprises a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) selected from at least two groups consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
2. The pharmaceutical product according to claim 1, wherein the antibiotic is selected from the following classes: amino acid derivatives, aminoglycosides, aureomycins, aziridines, ansamycins, benzenes, benzimidazoles, carbapenems, cephalosporins, coumarin-glycosides, diphenyl ether derivatives, diketopiperazines, fatty acid derivatives, glucosamine, glycopeptides, imidazoles, indole derivatives, lipopeptides, macrocyclic lactams, macrolides, nucleosides, penicillins and cephalosporins (β -lactams), peptides, peptidyl nucleosides, chloramphenicol, polyenes, polyethers, pyridines and pyrimidines, quinolones and fluoroquinolones, statins, steroids, sulfonamides, taxol and tetracyclines.
3. The pharmaceutical product according to claim 2, wherein the antibiotic is selected from the following classes: ansamycins, penicillins, cephalosporins, carbapenems and lipopeptides.
4. The pharmaceutical product of claim 1, wherein the antigenic agents are selected from at least four of groups (A), (B), (C), (D), (E) and (F).
5. The pharmaceutical product of claim 1, comprising 4-20 antigenic agents selected from the group consisting of antigenic agents derived from: streptococci, levedorin, candida, purified protein derivatives of coryza (PPD), prions, streptokinases, streptococci toxoid, diphtheria toxoid, tetanus toxoid, coxsackie tuberculin, inactivated ascaris lumbricoides lysate, aspergillus flavus, aspergillus fumigatus, aspergillus terreus, candida albicans, candida glabrata, candida parapsilosis, chlamydia pneumoniae, chlamydia psittaci, chlamydia trachomatis, cryptosporidium, dermatophytes, entamoebium histolyticum, enterobiasis vermicularia, enterococcus faecalis, mylophyton floccosum, escherichia coli, giardia lamblia, haemophilus influenzae, microsporum canis, mycobacterium bovis, mycobacterium leprae, mycobacterium tuberculosis, neisseria gonorrhoeae, human papilloma virus, poliovirus, certain species of proteus, proteus mirabilis, mycobacterium paraguayuri, mycobacterium phlei, mycobacterium, Proteus penonii, proteus vulgaris, salmonella bongofer, salmonella enteritidis, serratia decondensa, serratia marcescens, shigella flexneri, shigella sonnei, staphylococcus aureus, staphylococcus epidermidis, strongyloides stercoralis, streptococcus bovis, streptococcus viridis, streptococcus equi, streptococcus pneumoniae, streptococcus pyogenes, toxoplasma gondii, trichomonas vaginalis, trichophyton rubrum, trichophyton paraplegitimum, trichophyton mentagrophytes, yellow fever virus, hepatitis b virus, epidemic virus, varicella zoster virus, smallpox virus, yagi virus, leprosy virus, blepharitis virus and vaccinia virus or synthetic analogues presenting pathogen-associated molecular patterns (PAMPs) and/or risk-associated molecular patterns (DAMPs) associated with these antigenic agents.
6. A method of treating sepsis and multidrug resistant bacterial infections in a human or animal comprising administering to the human or animal an effective amount of one or more antibiotics and one or more IRS immunogenic compositions comprising a therapeutically effective amount of three or more synthetic or natural antigenic agents, or parts and combinations thereof, and one or more physiologically acceptable carriers, excipients, diluents, or solvents; the synthetic or natural antigenic agent comprises a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) selected from at least two groups consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
7. A method of modulating immune system response in a human or animal with a bacterial infection comprising administering to the human or animal an effective amount of one or more IRS immunogenic compositions comprising a therapeutically effective amount of three or more synthetic or natural antigenic agents, or parts and combinations thereof, and one or more physiologically acceptable carriers, excipients, diluents, or solvents; the synthetic or natural antigenic agent comprises a pathogen-associated molecular pattern (PAMP) and/or a risk-associated molecular pattern (DAMP) selected from at least two groups consisting of: (A) an antigenic agent having a molecular pattern associated with bacteria, (B) an antigenic agent having a molecular pattern associated with viruses, (C) an antigenic agent having a molecular pattern associated with fungi and yeasts, (D) an antigenic agent having a molecular pattern associated with protozoa, (E) an antigenic agent having a molecular pattern associated with helminths, and (F) an antigenic agent having a molecular pattern associated with prions.
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